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Tanaka S, Umeda M, Ujike H, Ryuko T, Tomioka Y, Miyoshi K, Okazaki M, Sugimoto S, Toyooka S. Novel pulmonary abdominal normothermic regional perfusion circuit for simultaneous in-donor evaluation and preservation of lungs and abdominal organs in donation after circulatory death. Gen Thorac Cardiovasc Surg 2025:10.1007/s11748-025-02137-y. [PMID: 40089938 DOI: 10.1007/s11748-025-02137-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/27/2025] [Indexed: 03/18/2025]
Abstract
OBJECTIVE To overcome limitations of traditional ex vivo lung perfusion (EVLP) for controlled donation after circulatory death (cDCD) lungs, this study aimed to evaluate a novel pulmonary abdominal normothermic regional perfusion (PANRP) technique, which we uniquely designed, for in situ assessment of lungs from cDCD donors. METHODS We modified the abdominal normothermic regional perfusion circuit for simultaneous lung and abdominal organ assessment using independent extracorporeal membrane oxygenation components. Blood was oxygenated via a membrane oxygenator and returned to the body, with pulmonary flow adjusted to maintain pressure < 25 mmHg. Femoral cannulation was performed, and the lungs were ventilated with standard settings. Organ function was assessed over 2 h using PaO2/FiO2, AST, ALT, BUN, and Cr measurements to monitor perfusion and oxygen delivery. RESULTS PANRP maintained stable lung function, with P/F ratios above 300, and preserved abdominal organ parameters, including stable AST, ALT, BUN, and Cr levels. Adequate urine output was observed, indicating normal renal function. Pulmonary artery pressure remained < 20 mmHg, and pulmonary vascular resistance was kept at 400 dyn・s/cm5, showing no signs of lung dysfunction or injury throughout the circuit. CONCLUSIONS PANRP offers a promising alternative to traditional EVLP for cDCD lung evaluation, allowing in situ assessment of multiple organs simultaneously. This approach may overcome logistical and economic challenges associated with ex vivo techniques, enabling a more efficient evaluation process. Further studies are warranted to confirm its clinical applicability and impact on long-term outcomes.
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Affiliation(s)
- Shin Tanaka
- Department of General Thoracic and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1, Shikata-cho, Kita-ku, Okayama, Japan.
| | - Masashi Umeda
- Department of General Thoracic and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1, Shikata-cho, Kita-ku, Okayama, Japan
| | - Hiroyuki Ujike
- Department of General Thoracic Surgery, Shimane University Graduate School of Medicine, Shimane, Japan
| | - Tsuyoshi Ryuko
- Department of General Thoracic and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1, Shikata-cho, Kita-ku, Okayama, Japan
| | - Yasuaki Tomioka
- Department of General Thoracic and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1, Shikata-cho, Kita-ku, Okayama, Japan
| | - Kentaroh Miyoshi
- Department of General Thoracic and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1, Shikata-cho, Kita-ku, Okayama, Japan
| | - Mikio Okazaki
- Department of General Thoracic and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1, Shikata-cho, Kita-ku, Okayama, Japan
| | - Seiichiro Sugimoto
- Department of General Thoracic and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1, Shikata-cho, Kita-ku, Okayama, Japan
| | - Shinichi Toyooka
- Department of General Thoracic and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1, Shikata-cho, Kita-ku, Okayama, Japan
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Nakata K, Alderete IS, Hughes BA, Hartwig MG. Ex vivo lung perfusion: recent advancements and future directions. Front Immunol 2025; 16:1513546. [PMID: 40066445 PMCID: PMC11891253 DOI: 10.3389/fimmu.2025.1513546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 02/05/2025] [Indexed: 05/13/2025] Open
Abstract
Ex-vivo lung perfusion (EVLP) has emerged as a transformative technique in lung transplantation, offering a solution for evaluating and rehabilitating donor lungs that would otherwise be deemed unsuitable. This review article examines the significant advancements in EVLP technology and its application in clinical practice. We discuss the criteria for selection and rehabilitation of donor lungs, emphasizing the use of EVLP for lungs with compromised function due to factors like prolonged ischemic time and donor smoking history. Further, we elaborate on the technological advancements that have improved the functional assessment of lungs, including the development of more sophisticated perfusion solutions and the integration of artificial intelligence for real-time assessment. Additionally, we discuss the future prospects of EVLP, focusing on potential innovations in perfusion solutions, the integration of regenerative medicine and gene therapy to improve allograft quality. Through this comprehensive review, we aim to provide a clear understanding of the current status of EVLP and its promising future directions, ultimately contributing to improved outcomes in lung transplantation.
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Affiliation(s)
- Kentaro Nakata
- Duke Ex Vivo Organ Laboratory, Department of Surgery, Duke University Medical
Center, Durham, NC, United States
| | - Isaac S. Alderete
- Duke Ex Vivo Organ Laboratory, Department of Surgery, Duke University Medical
Center, Durham, NC, United States
| | - Benjamin A. Hughes
- Duke Ex Vivo Organ Laboratory, Department of Surgery, Duke University Medical
Center, Durham, NC, United States
| | - Matthew G. Hartwig
- Duke Ex Vivo Organ Laboratory, Department of Surgery, Duke University Medical
Center, Durham, NC, United States
- Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, NC, United States
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Kukreja J, Campo-Canaveral de la Cruz JL, Van Raemdonck D, Cantu E, Date H, D'Ovidio F, Hartwig M, Klapper JA, Kelly RF, Lindstedt S, Rosso L, Schaheen L, Smith M, Whitson B, Saddoughi SA, Cypel M. The 2024 American Association for Thoracic Surgery expert consensus document: Current standards in donor lung procurement and preservation. J Thorac Cardiovasc Surg 2025; 169:484-504. [PMID: 39826938 DOI: 10.1016/j.jtcvs.2024.08.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 08/18/2024] [Accepted: 08/25/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Donor lung procurement and preservation is critical for lung transplantation success. Unfortunately, the large variability in techniques impacts organ utilization rates and transplantation outcomes. Compounding this variation, recent developments in cold static preservation and new technological advances with machine perfusion have increased the complexity of the procedure. The objective of the American Association for Thoracic Surgery (AATS) Clinical Practice Standards Committee (CPSC) expert panel was to make evidence-based recommendations for best practices in donor lung procurement and preservation based on review of the existing literature. METHODS The AATS CPSC assembled an expert panel of 16 lung transplantation surgeons from 14 centers who developed a consensus document of recommendations. The panel was divided into 7 subgroups covering (1) intraoperative donor assessment, (2) surgical techniques, (3) ex situ static lung preservation methods, (4) hypothermic preservation, (5) normothermic ex vivo lung perfusion (EVLP), (6) donation after circulatory death (DCD) and normothermic regional perfusion, and (7) donor management centers, organ assessment centers, and third-party procurement teams. Following a focused literature review, each subgroup formulated recommendation statements for each subtopic, which were reviewed and further refined using a Delphi process until a 75% consensus was achieved on each final statement by the voting group. RESULTS The expert panel achieved consensus on 34 recommendations for current best practices in donor lung procurement and preservation both in brain-dead as well as DCD donation. The use of new methods of cold preservation, the role of EVLP, and DCD with and without concomitant heart donation are described in detail. CONCLUSIONS Consistent and best practices in donor lung procurement and preservation are critical to improve both lung transplantation numbers as well as recipient outcomes. The recommendations described here provide guidance for professionals involved in the care of patients with end-stage lung disease considered for transplantation.
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Affiliation(s)
- Jasleen Kukreja
- Department of Surgery, University of California, San Francisco, Calif.
| | | | - Dirk Van Raemdonck
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Edward Cantu
- Department of Surgery, Hospital of the University of Pennsylvania, Philadephia, Pa
| | - Hiroshi Date
- Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Frank D'Ovidio
- Division of Thoracic Surgery, Columbia University Medical Center, New York, NY
| | - Matthew Hartwig
- Department of Surgery, Duke University Medical Center, Durham, NC
| | - Jacob A Klapper
- Department of Surgery, Duke University Medical Center, Durham, NC
| | - Rosemary F Kelly
- Division of CardioThoracic Surgery, University of Minnesota, Minneapolis, Minn
| | - Sandra Lindstedt
- Division of Thoracic Surgery, Skane University Hospital, Lund, Sweden
| | - Lorenzo Rosso
- Department of Pathophysiology and Transplantation, Fondazione IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Lara Schaheen
- St Joseph's Hospital and Medical Center, Phoenix, Ariz
| | - Michael Smith
- St Joseph's Hospital and Medical Center, Phoenix, Ariz
| | - Bryan Whitson
- Division of Cardiac Surgery, Ohio State University Medical Center, Columbus, Ohio
| | | | - Marcelo Cypel
- Division of Thoracic Surgery, University of Toronto, Toronto, Ontario, Canada.
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Yin V, Atay SM, Rodman JCS, Wightman SC, Rosenberg GM, Udelsman BV, Kim AW, Harano T. Impact of Ex Vivo Lung Perfusion on Inpatient Cost: A Propensity Score-Matched Analysis of the US Nationwide Healthcare Cost and Utilization Project Database. Clin Transplant 2025; 39:e70096. [PMID: 39876610 DOI: 10.1111/ctr.70096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 01/12/2025] [Accepted: 01/22/2025] [Indexed: 01/30/2025]
Abstract
BACKGROUND The goal of this study was to investigate the association between ex vivo lung perfusion (EVLP) use and inpatient hospitalization cost for lung transplantation in a nationwide sample. METHODS Lung transplantation patients in 2018-2020 Nationwide Readmissions Database (NRD) were grouped based on use of EVLP. The primary outcome was total inpatient hospitalization cost. 1:2 propensity score matching by EVLP status was performed followed by multivariable linear regression to determine the association between inpatient cost and EVLP while adjusting for pre-transplant hospital days, high volume EVLP center status, and propensity score. RESULTS There were 3902 lung transplants and 118 (3%) were recipients of EVLP lungs. Among EVLP patients, the median cost was $871 468 (IQR: $608 671-1 274 392), compared to $846 516 (IQR: $531 462-1 439 267, p = 0.871) among the total non-EVLP cohort. After 1:2 propensity score-matched cohort, recipients of EVLP lungs had longer median hospital length of stay (p = 0.046). In the multivariable model using the matched sample, increased cost was not associated with EVLP use (p = 0.783); however, high volume EVLP centers were associated with decreased cost (p = 0.018). CONCLUSIONS EVLP use was not associated with greater inpatient costs and may be favorable at high volume centers.
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Affiliation(s)
- Victoria Yin
- Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - Scott M Atay
- Division of Thoracic Surgery, Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - John C S Rodman
- Biostatistics, Epidemiology, and Research Design, Southern California Clinical and Translational Science Institute, The University of Southern California, Los Angeles, California, USA
| | - Sean C Wightman
- Division of Thoracic Surgery, Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Graeme M Rosenberg
- Division of Thoracic Surgery, Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Brooks V Udelsman
- Division of Thoracic Surgery, Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Anthony W Kim
- Division of Thoracic Surgery, Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Takashi Harano
- Division of Thoracic Surgery, Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
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Amarelli C, Bello I, Aigner C, Berman M, Boffini M, Clark S, Dalvindt M, de Wolf J, Ensminger S, Gomez de Antonio D, Hoyos L, Palmieri L, Schweiger M, Sponga S, Wiegmann B, Neyrinck A. European Society of Organ Transplantation (ESOT) Consensus Statement on Machine Perfusion in Cardiothoracic Transplant. Transpl Int 2024; 37:13112. [PMID: 39649067 PMCID: PMC11620879 DOI: 10.3389/ti.2024.13112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 09/26/2024] [Indexed: 12/10/2024]
Abstract
The machine perfusion (MP) of transplantable grafts has emerged as an upcoming field in Cardiothoracic (CT) transplantation during the last decade. This technology carries the potential to assess, preserve, and even recondition thoracic grafts before transplantation, so it is a possible game-changer in the field. This technology field has reached a critical turning point, with a growing number of publications coming predominantly from a few leading institutions, but still need solid scientific evidence. Due to the increasing need to expand the donor pool, especially in Europe, where the donor age is steeply increased, a consensus has been established to address the growing need and knowledge of machine perfusion in cardiothoracic transplantation, targeting the unmet scientific need in this growing field but also, priorities for development, and regional differences in utilization rates and organizational issues. To address MP in CT, the European Society of Organ Transplantation (ESOT) convened a dedicated Working group comprised of experts in CT to review literature about MP to develop guidelines that were subsequently discussed and voted on during the Consensus Conference that took place in person in Prague during the TLJ 3.0 in November 2022. The findings and recommendations of the Cardiothoracic Working Group on MP are presented in this article.
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Affiliation(s)
- Cristiano Amarelli
- Department of Cardiac Surgery and Transplants, Monaldi, Azienda dei Colli, Naples, Italy
| | - Irene Bello
- Institut Clínic Respiratorio, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Clemens Aigner
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Marius Berman
- Transplant Unit, Royal Papworth Hospital, NHS Foundation Trust, Cambridge, United Kingdom
| | - Massimo Boffini
- Cardiac Surgery Division, Surgical Sciences Department, Citta della Salute e della Scienza, University of Torino, Turin, Italy
| | - Stephen Clark
- Department Cardiothoracic Transplant, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Marita Dalvindt
- Department of Cardiothoracic Surgery, Lund University, Lund, Sweden
| | - Julien de Wolf
- Department of Thoracic Surgery, Lung Heart Institute, University Hospital of Lille, Lille, France
| | - Stephan Ensminger
- Department of Cardiac and Thoracic Vascular Surgery, University Heart Center Lübeck, Lübeck, Germany
| | - David Gomez de Antonio
- Department of Thoracic Surgery, Puerta de Hierro University Hospital Majadahonda, Madrid, Spain
| | - Lucas Hoyos
- Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Lucrezia Palmieri
- Department of Translational Medical Sciences, Monaldi Hospital, University of Campania “Luigi Vanvitelli“, Naples, Italy
| | - Martin Schweiger
- Department of Congenital Cardiovascular Surgery, Pediatric Heart Center, University Children’s Hospital Zurich, Zurich, Switzerland
| | - Sandro Sponga
- Division of Cardiac Surgery, Cardiothoracic Department, University Hospital of Udine, Udine, Italy
| | - Bettina Wiegmann
- Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hanover, Germany
| | - Arne Neyrinck
- Department of Cardiovascular Sciences, Anesthesiology and Algology, KU Leuven, Leuven, Belgium
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Mammana M, Zambello G, Pezzuto F, Faggi G, Dedja A, Faccioli E, Schiavon M, Calabrese F, Rea F. Comparison of Ex Vivo Lung Perfusion, With or Without Albumin, With Static Cold Storage in a Rat Ex Vivo Lung Perfusion Model. EXP CLIN TRANSPLANT 2024; 22:865-874. [PMID: 39663793 DOI: 10.6002/ect.2024.0185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2024]
Abstract
Ex vivo lung perfusion is an alternative to static cold storage for lung preservation in clinical lung transplantation. This study aimed to compare ex vivo lung perfusion with an acellular solution versus static cold storage and to assess the role of albumin as an additive to the acellular perfusion solution. Rat heart-lung blocks from Sprague-Dawley rats, after 1 hour of warm ischemia, were immersed in a low-potassium dextran solution for another hour. Blocks were then placed on ex vivo lung perfusion for 3 hours, with or without the addition of 70 g/L of albumin. Parameters such as gas exchange, dynamic lung compliance, and pulmonary vascular resistance were evaluated every 30 minutes. Control lungs were preserved in low-potassium dextran solution at 4 °C for 4 hours (static cold storage group). Lung injury was assessed using wet-to-dry ratio, histology, immunohistochemistry, and TUNEL assay. Pulmonary vascular resistance significantly decreased between 30 and 60 minutes of ex vivo lung perfusion, whereas other lung function parameters remained stable throughout the 3 hours. No significant differences were observed between the ex vivo lung perfusion and ex vivo lung perfusion + albumin groups in terms of lung function or pathology assessment. Pathological findings indicated that ex vivo lung perfusion, with or without albumin, resulted in increased edema and apoptotic activity compared with lungs preserved by static cold storage. The addition of albumin to the ex vivo lung perfusion solution did not result in significant improvements in functional parameters or pathological findings.
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Affiliation(s)
- Marco Mammana
- From the Department of Cardiac, Thoracic, Vascular Sciences, and Public Health-DCTV, Padua University Hospital, Padua, Italy; and the L.i.f.e.L.a.b. Program, Consorzio per la Ricerca Sanitaria (CORIS), Veneto Region, Padova, Italy
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Aburahma K, de Manna ND, Kuehn C, Salman J, Greer M, Ius F. Pushing the Survival Bar Higher: Two Decades of Innovation in Lung Transplantation. J Clin Med 2024; 13:5516. [PMID: 39337005 PMCID: PMC11432129 DOI: 10.3390/jcm13185516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/13/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Survival after lung transplantation has significantly improved during the last two decades. The refinement of the already existing extracorporeal life support (ECLS) systems, such as extracorporeal membrane oxygenation (ECMO), and the introduction of new techniques for donor lung optimization, such as ex vivo lung perfusion (EVLP), have allowed the extension of transplant indication to patients with end-stage lung failure after acute respiratory distress syndrome (ARDS) and the expansion of the donor organ pool, due to the better evaluation and optimization of extended-criteria donor (ECD) lungs and of donors after circulatory death (DCD). The close monitoring of anti-HLA donor-specific antibodies (DSAs) has allowed the early recognition of pulmonary antibody-mediated rejection (AMR), which requires a completely different treatment and has a worse prognosis than acute cellular rejection (ACR). As such, the standardization of patient selection and post-transplant management has significantly contributed to this positive trend, especially at high-volume centers. This review focuses on lung transplantation after ARDS, on the role of EVLP in lung donor expansion, on ECMO as a principal cardiopulmonary support system in lung transplantation, and on the diagnosis and therapy of pulmonary AMR.
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Affiliation(s)
- Khalil Aburahma
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
| | - Nunzio Davide de Manna
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
| | - Christian Kuehn
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
- German Centre for Lung Research (DZL/BREATH), 35392 Hannover, Germany
| | - Jawad Salman
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
- German Centre for Lung Research (DZL/BREATH), 35392 Hannover, Germany
| | - Mark Greer
- German Centre for Lung Research (DZL/BREATH), 35392 Hannover, Germany
- Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, 30625 Hannover, Germany
| | - Fabio Ius
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
- German Centre for Lung Research (DZL/BREATH), 35392 Hannover, Germany
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8
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Gouchoe DA, Sanchez PG, D'Cunha J, Bermudez CA, Daneshmand MA, Davis RD, Hartwig MG, Wozniak TC, Kon ZN, Griffith BP, Lynch WR, Machuca TN, Weyant MJ, Jessen ME, Mulligan MS, D'Ovidio F, Camp PC, Cantu E, Whitson BA. Ex vivo lung perfusion in donation after circulatory death: A post hoc analysis of the Normothermic Ex Vivo Lung Perfusion as an Assessment of Extended/Marginal Donors Lungs trial. J Thorac Cardiovasc Surg 2024; 168:724-734.e7. [PMID: 38508486 DOI: 10.1016/j.jtcvs.2024.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/06/2024] [Accepted: 03/06/2024] [Indexed: 03/22/2024]
Abstract
OBJECTIVE Donation after circulatory death (DCD) donors offer the ability to expand the lung donor pool and ex vivo lung perfusion (EVLP) further contributes to this ability by allowing for additional evaluation and resuscitation of these extended criteria donors. We sought to determine the outcomes of recipients receiving organs from DCD EVLP donors in a multicenter setting. METHODS This was an unplanned post hoc analysis of a multicenter, prospective, nonrandomized trial that took place during 2011 to 2017 with 3 years of follow-up. Patients were placed into 3 groups based off procurement strategy: brain-dead donor (control), brain-dead donor evaluated by EVLP, and DCD donors evaluated by EVLP. The primary outcomes were severe primary graft dysfunction at 72 hours and survival. Secondary outcomes included select perioperative outcomes, and 1-year and 3-years allograft function and quality of life measures. RESULTS The DCD EVLP group had significantly higher incidence of severe primary graft dysfunction at 72 hours (P = .03), longer days on mechanical ventilation (P < .001) and in-hospital length of stay (P = .045). Survival at 3 years was 76.5% (95% CI, 69.2%-84.7%) for the control group, 68.3% (95% CI, 58.9%-79.1%) for the brain-dead donor group, and 60.7% (95% CI, 45.1%-81.8%) for the DCD group (P = .36). At 3-year follow-up, presence observed bronchiolitis obliterans syndrome or quality of life metrics did not differ among the groups. CONCLUSIONS Although DCD EVLP allografts might not be appropriate to transplant in every candidate recipient, the expansion of their use might afford recipients stagnant on the waitlist a viable therapy.
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Affiliation(s)
- Doug A Gouchoe
- Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Center, College of Medicine, Columbus, Ohio; 88th Surgical Operations Squadron, Wright-Patterson Medical Center, Wright-Patterson Air Force Base, Ohio
| | - Pablo G Sanchez
- Division of Thoracic Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa
| | - Jonathan D'Cunha
- Department of Cardiothoracic Surgery, Mayo Clinic Arizona, Phoenix, Ariz
| | | | - Mani A Daneshmand
- Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, Ga
| | - Robert D Davis
- Department of Cardiovascular and Thoracic Surgery, Florida Hospital Transplant Center, Orlando, Fla
| | - Matthew G Hartwig
- Division of Cardiovascular and Thoracic Surgery, Duke University School of Medicine, Durham, NC
| | - Thomas C Wozniak
- Division of Cardiothoracic Surgery, ProHealth Care, Waukesha, Wis
| | - Zachary N Kon
- Division of Cardiothoracic Surgery, Department of Surgery, Northwell Health, Manhasset, NY
| | - Bartley P Griffith
- Department of Cardiac Surgery, University of Maryland Medical Center, Baltimore, Md
| | - William R Lynch
- Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, Mich
| | - Tiago N Machuca
- Division of Lung Transplantation, Department of Surgery, University of Miami Miller School of Medicine, Miami, Fla
| | | | - Michael E Jessen
- Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern, Dallas, Tex
| | - Michael S Mulligan
- Division of Cardiothoracic Surgery, Department of Surgery, University of Washington, Seattle, Wash
| | - Frank D'Ovidio
- Section of General Thoracic Surgery, Lung Transplant Program, Columbia University Medical Center, New York, NY
| | - Phillip C Camp
- Department of Cardiothoracic Surgery, Corewell Health-East, Dearborn, Mich
| | - Edward Cantu
- Division of Cardiac Surgery, University of Pennsylvania, Philadelphia, Pa
| | - Bryan A Whitson
- Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Center, College of Medicine, Columbus, Ohio; Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory, The Ohio State University, Columbus, Ohio; The Davis Heart and Lung Research Institute, The Ohio State University Wexner Center, College of Medicine, Columbus, Ohio.
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9
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Niroomand A, Nita GE, Lindstedt S. Machine Perfusion and Bioengineering Strategies in Transplantation-Beyond the Emerging Concepts. Transpl Int 2024; 37:13215. [PMID: 39267617 PMCID: PMC11390383 DOI: 10.3389/ti.2024.13215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 08/19/2024] [Indexed: 09/15/2024]
Abstract
Solid organ transplantation has progressed rapidly over the decades from the first experimental procedures to its role in the modern era as an established treatment for end-stage organ disease. Solid organ transplantation including liver, kidney, pancreas, heart, and lung transplantation, is the definitive option for many patients, but despite the advances that have been made, there are still significant challenges in meeting the demand for viable donor grafts. Furthermore, post-operatively, the recipient faces several hurdles, including poor early outcomes like primary graft dysfunction and acute and chronic forms of graft rejection. In an effort to address these issues, innovations in organ engineering and treatment have been developed. This review covers efforts made to expand the donor pool including bioengineering techniques and the use of ex vivo graft perfusion. It also covers modifications and treatments that have been trialed, in addition to research efforts in both abdominal organs and thoracic organs. Overall, this article discusses recent innovations in machine perfusion and organ bioengineering with the aim of improving and increasing the quality of donor organs.
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Affiliation(s)
- Anna Niroomand
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
- Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital, Lund, Sweden
| | - George Emilian Nita
- Department of Transplantation Surgery, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
- Division of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Sandra Lindstedt
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
- Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital, Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
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10
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Rose J, Gunsalus PR, Lehr CJ, Swiler MF, Dalton JE, Valapour M. A modular simulation framework for organ allocation. J Heart Lung Transplant 2024; 43:1326-1335. [PMID: 38705499 PMCID: PMC11261589 DOI: 10.1016/j.healun.2024.04.063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 03/26/2024] [Accepted: 04/25/2024] [Indexed: 05/07/2024] Open
Abstract
BACKGROUND We describe and validate a new simulation framework addressing important limitations of the Simulated Allocation Models (SAMs) long used to project population effects of transplant policy changes. METHODS We developed the Computational Open-source Model for Evaluating Transplantation (COMET), an agent-based model simulating interactions of individual donors and candidates over time to project population outcomes. COMET functionality is organized into interacting modules. Donors and candidates are synthetically generated using data-driven probability models which are adaptable to account for ongoing or hypothetical donor/candidate population trends and evolving disease management. To validate the first implementation of COMET, COMET-Lung, we attempted to reproduce lung transplant outcomes for U.S. adults from 2018-2019 and in the 6 months following adoption of the Composite Allocation Score (CAS) for lung transplant. RESULTS Simulated (median [Interquartile Range, IQR]) vs observed outcomes for 2018-2019 were: 0.162 [0.157, 0.167] vs 0.170 waitlist deaths per waitlist year; 1.25 [1.23, 1.28] vs 1.26 transplants per waitlist year; 0.115 [0.112, 0.118] vs 0.113 post-transplant deaths per patient year; 202 [102, 377] vs 165 nautical miles travel distance. The model accurately predicted the observed precipitous decrease in transplants received by type O lung candidates in the six months following CAS implementation. CONCLUSIONS COMET-Lung closely reproduced most observed outcomes. The use of synthetic populations in the COMET framework paves the way for examining possible transplant policy and clinical practice changes in populations reflecting realistic future states. Its flexible, modular nature can accelerate development of features to address specific research or policy questions across multiple organs.
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Affiliation(s)
- Johnie Rose
- Center for Community Health Integration, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Paul R Gunsalus
- Center for Populations Health Research, Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Carli J Lehr
- Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA; Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Mark F Swiler
- Center for Populations Health Research, Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jarrod E Dalton
- Center for Populations Health Research, Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA; Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Maryam Valapour
- Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA.
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11
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Chan CHH, Farooqui A, Al-Sahli H, Elsenousi A, Mattar A, Wang Y, Loor G. Development of a Novel Optimized BioEnvironment for proLonged (NOBEL) ex vivo lung preservation. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2024; 2024:1-4. [PMID: 40039104 DOI: 10.1109/embc53108.2024.10782017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
Current Ex Vivo Lung Perfusion (EVLP) systems are designed to support lungs outside of the body for up to 12 hours, allowing clinicians limited opportunity to assess organ function and viability prior to transplant. However, prolonged EVLP would allow for advanced time-dependent therapies such as immunomodulation, cell-based therapies and gene editing for donor lung repair and reconditioning. Therefore, we have developed a novel optimized bioenvironment for prolonged (NOBEL) EVLP to preserve a donor lung up to 30 hours. Three healthy swine donor lungs were used to optimize our NOBEL EVLP system. Several improvements over conventional blood-based EVLP protocols were used to prolong preservation including the following: (a) hypothermia to reduce metabolic waste and hemolysis, (b) dialysis to maintain pH, glucose and electrolyte levels at normal values, (c) proning using a biocompatible soft net lung support with axial lung rotation to reduce positional lung tissue damage, and (d) total parenteral nutrition to provide vital nutrients for cellular recovery. Our preliminary results show that these interventions were associated with improved lung oxygenation and gross morphology over that seen with a conventional EVLP protocol.
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12
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Iskender I. Technical Advances Targeting Multiday Preservation of Isolated Ex Vivo Lung Perfusion. Transplantation 2024; 108:1319-1332. [PMID: 38499501 DOI: 10.1097/tp.0000000000004992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2024]
Abstract
Indications for ex vivo lung perfusion (EVLP) have evolved from assessment of questionable donor lungs to treatment of some pathologies and the logistics. Yet up to 3 quarters of donor lungs remain discarded across the globe. Multiday preservation of discarded human lungs on EVLP platforms would improve donor lung utilization rates via application of sophisticated treatment modalities, which could eventually result in zero waitlist mortality. The purpose of this article is to summarize advances made on the technical aspects of the protocols in achieving a stable multiday preservation of isolated EVLP. Based on the evidence derived from large animal and/or human studies, the following advances have been considered important in achieving this goal: ability to reposition donor lungs during EVLP; perfusate adsorption/filtration modalities; perfusate enrichment with plasma and/or donor whole blood, nutrients, vitamins, and amino acids; low-flow, pulsatile, and subnormothermic perfusion; positive outflow pressure; injury specific personalized ventilation strategies; and negative pressure ventilation. Combination of some of these advances in an automatized EVLP device capable of managing perfusate biochemistry and ventilation would likely speed up the processes of achieving multiday preservation of isolated EVLP.
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Affiliation(s)
- Ilker Iskender
- Department of Cardiac Surgery, East Limburg Hospital, Genk, Belgium
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13
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Staibano P, Oulousian E, McKechnie T, Thabane A, Luo S, Gupta MK, Zhang H, Pasternak JD, Au M, Parpia S, Young JEM(T, Bhandari M. Adaptive clinical trials in surgery: A scoping review of methodological and reporting quality. PLoS One 2024; 19:e0299494. [PMID: 38805454 PMCID: PMC11132449 DOI: 10.1371/journal.pone.0299494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 02/11/2024] [Indexed: 05/30/2024] Open
Abstract
IMPORTANCE Adaptive surgical trials are scarce, but adopting these methods may help elevate the quality of surgical research when large-scale RCTs are impractical. OBJECTIVE Randomized-controlled trials (RCTs) are the gold standard for evidence-based healthcare. Despite an increase in the number of RCTs, the number of surgical trials remains unchanged. Adaptive clinical trials can streamline trial design and time to trial reporting. The advantages identified for ACTs may help to improve the quality of future surgical trials. We present a scoping review of the methodological and reporting quality of adaptive surgical trials. EVIDENCE REVIEW We performed a search of Ovid, Web of Science, and Cochrane Collaboration for all adaptive surgical RCTs performed from database inception to October 12, 2023. We included any published trials that had at least one surgical arm. All review and abstraction were performed in duplicate. Risk of bias (RoB) was assessed using the RoB 2.0 instrument and reporting quality was evaluated using CONSORT ACE 2020. All results were analyzed using descriptive methods. FINDINGS Of the 1338 studies identified, six trials met inclusion criteria. Trials were performed in cardiothoracic, oral, orthopedic, and urological surgery. The most common type of adaptive trial was group sequential design with pre-specified interim analyses planned for efficacy, futility, and/or sample size re-estimation. Two trials did use statistical simulations. Our risk of bias evaluation identified a high risk of bias in 50% of included trials. Reporting quality was heterogeneous regarding trial design and outcome assessment and details in relation to randomization and blinding concealment. CONCLUSION AND RELEVANCE Surgical trialists should consider implementing adaptive components to help improve patient recruitment and reduce trial duration. Reporting of future adaptive trials must adhere to existing CONSORT ACE 2020 guidelines. Future research is needed to optimize standardization of adaptive methods across medicine and surgery.
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Affiliation(s)
- Phillip Staibano
- Division of Otolaryngology–Head and Neck Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
- Department of Health Research Methodology, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Emily Oulousian
- Division of Otolaryngology–Head and Neck Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
- McGill University School of Medicine, McGill University, Montreal, Quebec, Canada
| | - Tyler McKechnie
- Department of Health Research Methodology, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Alex Thabane
- Department of Health Research Methodology, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Samuel Luo
- Division of Otolaryngology–Head and Neck Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
- Michael G. DeGroote School of Medicine, Hamilton, Ontario, Canada
| | - Michael K. Gupta
- Division of Otolaryngology–Head and Neck Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Han Zhang
- Division of Otolaryngology–Head and Neck Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Jesse D. Pasternak
- Endocrine Surgery Section Head, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Michael Au
- Division of Otolaryngology–Head and Neck Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Sameer Parpia
- Department of Health Research Methodology, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - J. E. M. (Ted) Young
- Division of Otolaryngology–Head and Neck Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Mohit Bhandari
- Department of Health Research Methodology, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Division of Orthopedic Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
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14
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Chao BT, McInnis MC, Sage AT, Yeung JC, Cypel M, Liu M, Wang B, Keshavjee S. A radiographic score for human donor lungs on ex vivo lung perfusion predicts transplant outcomes. J Heart Lung Transplant 2024; 43:797-805. [PMID: 38211838 DOI: 10.1016/j.healun.2024.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 01/02/2024] [Accepted: 01/05/2024] [Indexed: 01/13/2024] Open
Abstract
BACKGROUND Ex vivo lung perfusion (EVLP) is an advanced platform for isolated lung assessment and treatment. Radiographs acquired during EVLP provide a unique opportunity to assess lung injury. The purpose of our study was to define and evaluate EVLP radiographic findings and their association with lung transplant outcomes. METHODS We retrospectively evaluated 113 EVLP cases from 2020-21. Radiographs were scored by a thoracic radiologist blinded to outcome. Six lung regions were scored for 5 radiographic features (consolidation, infiltrates, atelectasis, nodules, and interstitial lines) on a scale of 0 to 3 to derive a score. Spearman's correlation was used to correlate radiographic scores to biomarkers of lung injury. Machine learning models were developed using radiographic features and EVLP functional data. Predictive performance was assessed using the area under the curve. RESULTS Consolidation and infiltrates were the most frequent findings at 1 hour EVLP (radiographic lung score 2.6 (3.3) and 4.6 (4.3)). Consolidation (r = -0.536 and -0.608, p < 0.0001) and infiltrates (r = -0.492 and -0.616, p < 0.0001) were inversely correlated with oxygenation (∆pO2) at 1 hour and 3 hours of EVLP. First-hour consolidation and infiltrate lung scores predicted transplant suitability with an area under the curve of 87% and 88%, respectively. Prediction of transplant outcomes using a machine learning model yielded an area under the curve of 80% in the validation set. CONCLUSIONS EVLP radiographs provide valuable insight into donor lungs being assessed for transplantation. Consolidation and infiltrates were the most common abnormalities observed in EVLP lungs, and radiographic lung scores predicted the suitability of donor lungs for transplant.
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Affiliation(s)
- Bonnie T Chao
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Micheal C McInnis
- University Medical Imaging Toronto, Toronto General Hospital, University Health Network, Toronto, ON, Canada; Department of Medical Imaging, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Andrew T Sage
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Jonathan C Yeung
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Marcelo Cypel
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Mingyao Liu
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Bo Wang
- Vector Institute, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Shaf Keshavjee
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
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15
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M M, Attawar S, BN M, Tisekar O, Mohandas A. Ex vivo lung perfusion and the Organ Care System: a review. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:23-36. [PMID: 38725180 PMCID: PMC11075812 DOI: 10.4285/ctr.23.0057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/29/2024] [Accepted: 03/08/2024] [Indexed: 05/14/2024]
Abstract
With the increasing prevalence of heart failure and end-stage lung disease, there is a sustained interest in expanding the donor pool to alleviate the thoracic organ shortage crisis. Efforts to extend the standard donor criteria and to include donation after circulatory death have been made to increase the availability of suitable organs. Studies have demonstrated that outcomes with extended-criteria donors are comparable to those with standard-criteria donors. Another promising approach to augment the donor pool is the improvement of organ preservation techniques. Both ex vivo lung perfusion (EVLP) for the lungs and the Organ Care System (OCS, TransMedics) for the heart have shown encouraging results in preserving organs and extending ischemia time through the application of normothermic regional perfusion. EVLP has been effective in improving marginal or borderline lungs by preserving and reconditioning them. The use of OCS is associated with excellent short-term outcomes for cardiac allografts and has improved utilization rates of hearts from extended-criteria donors. While both EVLP and OCS have successfully transitioned from research to clinical practice, the costs associated with commercially available systems and consumables must be considered. The ex vivo perfusion platform, which includes both EVLP and OCS, holds the potential for diverse and innovative therapies, thereby transforming the landscape of thoracic organ transplantation.
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Affiliation(s)
- Menander M
- Institute of Heart and Lung Transplant, Krishna Institute of Medical Sciences (KIMS) Hospital, Secunderabad, India
| | - Sandeep Attawar
- Institute of Heart and Lung Transplant, Krishna Institute of Medical Sciences (KIMS) Hospital, Secunderabad, India
| | - Mahesh BN
- Institute of Heart and Lung Transplant, Krishna Institute of Medical Sciences (KIMS) Hospital, Secunderabad, India
| | - Owais Tisekar
- Institute of Heart and Lung Transplant, Krishna Institute of Medical Sciences (KIMS) Hospital, Secunderabad, India
| | - Anoop Mohandas
- Institute of Heart and Lung Transplant, Krishna Institute of Medical Sciences (KIMS) Hospital, Secunderabad, India
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16
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Gunsalus PR, Rose J, Lehr CJ, Valapour M, Dalton JE. Creating synthetic populations in transplantation: A Bayesian approach enabling simulation without registry re-sampling. PLoS One 2024; 19:e0296839. [PMID: 38512928 PMCID: PMC10956776 DOI: 10.1371/journal.pone.0296839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 12/20/2023] [Indexed: 03/23/2024] Open
Abstract
Computer simulation has played a pivotal role in analyzing alternative organ allocation strategies in transplantation. The current approach to producing cohorts of organ donors and candidates for individual-level simulation requires directly re-sampling retrospective data from a transplant registry. This historical data may reflect outmoded policies and practices as well as systemic inequities in candidate listing, limiting contemporary applicability of simulation results. We describe the development of an alternative approach for generating synthetic donors and candidates using hierarchical Bayesian network probability models. We developed two Bayesian networks to model dependencies among 10 donor and 36 candidate characteristics relevant to waitlist survival, donor-candidate matching, and post-transplant survival. We estimated parameters for each model using Scientific Registry of Transplant Recipients (SRTR) data. For 100 donor and 100 candidate synthetic populations generated, proportions for each categorical donor or candidate attribute, respectively, fell within one percentage point of observed values; the interquartile ranges (IQRs) of each continuous variable contained the corresponding SRTR observed median. Comparisons of synthetic to observed stratified distributions demonstrated the ability of the method to capture complex joint variability among multiple characteristics. We also demonstrated how changing two upstream population parameters can exert cascading effects on multiple relevant clinical variables in a synthetic population. Generating synthetic donor and candidate populations in transplant simulation may help overcome critical limitations related to the re-sampling of historical data, allowing developers and decision makers to customize the parameters of these populations to reflect realistic or hypothetical future states.
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Affiliation(s)
- Paul R. Gunsalus
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States of America
| | - Johnie Rose
- Center for Community Health Integration, Case Western Reserve University, Cleveland, OH, United States of America
| | - Carli J. Lehr
- Department of Pulmonary Medicine, Cleveland Clinic, Cleveland, OH, United States of America
| | - Maryam Valapour
- Department of Pulmonary Medicine, Cleveland Clinic, Cleveland, OH, United States of America
| | - Jarrod E. Dalton
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States of America
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17
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Buttar SN, Schultz HHL, Møller-Sørensen H, Perch M, Petersen RH, Møller CH. Long-term outcomes of lung transplantation with ex vivo lung perfusion technique. FRONTIERS IN TRANSPLANTATION 2024; 3:1324851. [PMID: 38993789 PMCID: PMC11235351 DOI: 10.3389/frtra.2024.1324851] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 01/18/2024] [Indexed: 07/13/2024]
Abstract
Ex vivo lung perfusion (EVLP) has demonstrated encouraging short- and medium-term outcomes with limited data available on its long-term outcomes. This study assesses (1) EVLP long-term outcomes and (2) EVLP era-based sub-analysis in addition to secondary outcomes of recipients with EVLP-treated donor lungs compared with recipients of conventionally preserved donor lungs in unmatched and propensity score-matched cohorts. Double lung transplants performed between 1st January 2012 and 31st December 2021 were included. A total of 57 recipients received EVLP-treated lungs compared to 202 unmatched and 57 matched recipients who were subjected to non-EVLP-treated lungs. The EVLP group had a significantly lower mean PaO2/FiO2 ratio and significantly higher mean BMI than the non-EVLP group in the unmatched and matched cohorts. The proportion of smoking history in the unmatched cohort was significantly higher in the EVLP group, while a similar smoking history was demonstrated in the matched cohorts. No difference was demonstrated in overall freedom from death and retransplantation between the groups in the unmatched and matched cohorts (unmatched: hazard ratio (HR) 1.28, 95% confidence interval (CI) 0.79-2.07, P = 0.32; matched: HR 1.06, 95% CI 0.59-1.89). P = 0.89). In the unmatched cohort, overall freedom from chronic allograft dysfunction (CLAD) was significantly different between the groups (HR 1.64, 95% CI 1.07-2.52, P = 0.02); however, the cumulative CLAD incidence was similar (HR 0.72, 95% CI 0.48-1.1, P = 0.13). In the matched cohort, the overall freedom from CLAD (HR 1.69, 95% CI 0.97-2.95, P = 0.06) and cumulative CLAD incidence (HR 0.91, 95% CI 0.37-2.215, P = 0.83) were similar between the groups. The EVLP era sub-analysis of the unmatched cohort in 2012-2014 had a significantly higher cumulative CLAD incidence in the EVLP group; however, this was not demonstrated in the matched cohort. All secondary outcomes were similar between the groups in the unmatched and matched cohorts. In conclusion, transplantation of marginal donor lungs after EVLP evaluation is non-detrimental compared to conventionally preserved donor lungs in terms of mortality, retransplantation, cumulative CLAD incidence, and secondary outcomes. Although the unmatched EVLP era of 2012-2014 had a significantly higher cumulative CLAD incidence, no such finding was demonstrated in the matched cohort of the same era.
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Affiliation(s)
- Sana N Buttar
- Department of Cardiothoracic Surgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Hans Henrik L Schultz
- Department of Cardiology, Section for Lung Transplantation, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Hasse Møller-Sørensen
- Department of Cardiothoracic Anaesthesiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Michael Perch
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Cardiology, Section for Lung Transplantation, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Rene Horsleben Petersen
- Department of Cardiothoracic Surgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Christian H Møller
- Department of Cardiothoracic Surgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Jenkins JA, Verdiner R, Omar A, Farina JM, Wilson R, D’Cunha J, Reck Dos Santos PA. Donor and recipient risk factors for the development of primary graft dysfunction following lung transplantation. Front Immunol 2024; 15:1341675. [PMID: 38380332 PMCID: PMC10876853 DOI: 10.3389/fimmu.2024.1341675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 01/22/2024] [Indexed: 02/22/2024] Open
Abstract
Primary Graft Dysfunction (PGD) is a major cause of both short-term and long-term morbidity and mortality following lung transplantation. Various donor, recipient, and technical risk factors have been previously identified as being associated with the development of PGD. Here, we present a comprehensive review of the current literature as it pertains to PGD following lung transplantation, as well as discussing current strategies to mitigate PGD and future directions. We will pay special attention to recent advances in lung transplantation such as ex-vivo lung perfusion, thoracoabdominal normothermic regional perfusion, and up-to-date literature published in the interim since the 2016 ISHLT consensus statement on PGD and the COVID-19 pandemic.
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Affiliation(s)
- J. Asher Jenkins
- Department of Cardiothoracic Surgery, Mayo Clinic Arizona, Phoenix, AZ, United States
| | - Ricardo Verdiner
- Department of Anesthesia and Perioperative Medicine, Mayo Clinic Arizona, Phoenix, AZ, United States
| | - Ashraf Omar
- Division of Pulmonology and Critical Care Medicine, Mayo Clinic Arizona, Phoenix, AZ, United States
| | - Juan Maria Farina
- Department of Cardiothoracic Surgery, Mayo Clinic Arizona, Phoenix, AZ, United States
| | - Renita Wilson
- Department of Cardiothoracic Surgery, Mayo Clinic Arizona, Phoenix, AZ, United States
| | - Jonathan D’Cunha
- Department of Cardiothoracic Surgery, Mayo Clinic Arizona, Phoenix, AZ, United States
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19
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Xia Y, Kim ST, Dacey M, Sayah D, Biniwale R, Ardehali A. Characteristics and outcomes of lung transplants performed with ex-situ lung perfusion. J Heart Lung Transplant 2024; 43:217-225. [PMID: 37643655 DOI: 10.1016/j.healun.2023.08.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 07/22/2023] [Accepted: 08/23/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Ex-situ lung perfusion (ESLP) can be used to assess and rehabilitate donor lungs, potentially expanding the donor pool. We examined the characteristics and outcomes of lung transplants performed with ESLP in the United States. METHODS Retrospective review of the United Network for Organ Sharing registry of primary adult lung transplant recipients from February 28, 2018, to June 30, 2021, was performed, comparing baseline characteristics, in-hospital outcomes, and 1-year survival of ESLP vs no ESLP lung transplants. RESULTS Of 8204 lung transplants, 426 (5.2%) were performed with ESLP. ESLP donors were older, more donation after circulatory death (DCD), and had lower PaO2:FiO2 (P:F) ratios. Recipients had lower lung allocation scores. ESLP lungs traveled further, had longer preservation times, and were more likely double lung transplants. Reintubation rates, extracorporeal membrane oxygenation at 72 hours, and hospital length of stay were greater in the ESLP group. On multivariable analysis, ESLP was not an independent predictor of 1-year survival. However, further analysis showed that DCD lungs managed on ESLP had worse 1-year survival compared to DCD lungs preserved with standard cold storage or with donation after brain death donor lungs. CONCLUSIONS ESLP is used in a small percentage of lung transplants in the US and is not independently associated with 1-year survival. ESLP combined with DCD lungs, however, is associated with worse 1-year survival and warrants further investigation.
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Affiliation(s)
- Yu Xia
- Department of Surgery, Division of Cardiothoracic Surgery, University of Wisconsin, Madison, Wisconsin.
| | - Samuel T Kim
- Department of Surgery, Division of Cardiac Surgery, University of California, Los Angeles, California
| | - Michael Dacey
- Department of Surgery, Division of Cardiac Surgery, University of California, Los Angeles, California
| | - David Sayah
- Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, Los Angeles, California
| | - Reshma Biniwale
- Department of Surgery, Division of Cardiac Surgery, University of California, Los Angeles, California
| | - Abbas Ardehali
- Department of Surgery, Division of Cardiac Surgery, University of California, Los Angeles, California
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20
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López-Martínez S, Simón C, Santamaria X. Normothermic Machine Perfusion Systems: Where Do We Go From Here? Transplantation 2024; 108:22-44. [PMID: 37026713 DOI: 10.1097/tp.0000000000004573] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Normothermic machine perfusion (NMP) aims to preserve organs ex vivo by simulating physiological conditions such as body temperature. Recent advancements in NMP system design have prompted the development of clinically effective devices for liver, heart, lung, and kidney transplantation that preserve organs for several hours/up to 1 d. In preclinical studies, adjustments to circuit structure, perfusate composition, and automatic supervision have extended perfusion times up to 1 wk of preservation. Emerging NMP platforms for ex vivo preservation of the pancreas, intestine, uterus, ovary, and vascularized composite allografts represent exciting prospects. Thus, NMP may become a valuable tool in transplantation and provide significant advantages to biomedical research. This review recaps recent NMP research, including discussions of devices in clinical trials, innovative preclinical systems for extended preservation, and platforms developed for other organs. We will also discuss NMP strategies using a global approach while focusing on technical specifications and preservation times.
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Affiliation(s)
- Sara López-Martínez
- Carlos Simon Foundation, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Carlos Simón
- Carlos Simon Foundation, Centro de Investigación Príncipe Felipe, Valencia, Spain
- Department of Obstetrics and Gynecology, Universidad de Valencia, Valencia, Spain
- Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX
| | - Xavier Santamaria
- Carlos Simon Foundation, Centro de Investigación Príncipe Felipe, Valencia, Spain
- INCLIVA Biomedical Research Institute, Valencia, Spain
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21
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Zhou AL, Larson EL, Ruck JM, Ha JS, Casillan AJ, Bush EL. Current status and future potential of ex vivo lung perfusion in clinical lung transplantation. Artif Organs 2023; 47:1700-1709. [PMID: 37455548 DOI: 10.1111/aor.14607] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/29/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023]
Abstract
Lung transplantation is accepted as a well-established and effective treatment for patients with end-stage lung disease. While the number of candidates added to the waitlist continues to rise, the number of transplants performed remains limited by the number of suitable organ donors. Ex vivo lung perfusion (EVLP) emerged as a method of addressing the organ shortage by allowing the evaluation and potential reconditioning of marginal donor lungs or minimizing risks of prolonged ischemic time due to logistical challenges. The currently available FDA-approved EVLP systems have demonstrated excellent outcomes in clinical trials, and retrospective studies have demonstrated similar post-transplant survival between recipients who received marginal donor lungs perfused using EVLP and recipients who received standard criteria lungs stored using conventional methods. Despite this, widespread utilization has plateaued in the last few years, likely due to the significant costs associated with initiating EVLP programs. Centralized, dedicated EVLP perfusion centers are currently being investigated as a potential method of further expanding utilization of this technology. In the preclinical setting, potential applications of EVLP that are currently being studied include prolongation of organ preservation, reconditioning of unsuitable lungs, and further enhancement of already suitable lungs. As adoption of EVLP technology becomes more widespread, we may begin to see future implementation of these potential applications into the clinical setting.
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Affiliation(s)
- Alice L Zhou
- Division of Thoracic Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Emily L Larson
- Division of Thoracic Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Jessica M Ruck
- Division of Thoracic Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Jinny S Ha
- Division of Thoracic Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Alfred J Casillan
- Division of Thoracic Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Errol L Bush
- Division of Thoracic Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA
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22
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Pither T, Wang L, Bates L, Morrison M, Charlton C, Griffiths C, Macdonald J, Bigley V, Mavridou M, Barsby J, Borthwick L, Dark J, Scott W, Ali S, Fisher AJ. Modeling the Effects of IL-1β-mediated Inflammation During Ex Vivo Lung Perfusion Using a Split Human Donor Model. Transplantation 2023; 107:2179-2189. [PMID: 37143202 PMCID: PMC10519297 DOI: 10.1097/tp.0000000000004613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 02/08/2023] [Accepted: 02/23/2023] [Indexed: 05/06/2023]
Abstract
BACKGROUND The association between interleukin-1β (IL-1β) concentrations during ex vivo lung perfusion (EVLP) with donor organ quality and post-lung transplant outcome has been demonstrated in several studies. The mechanism underlying IL-1β-mediated donor lung injury was investigated using a paired single-lung EVLP model. METHODS Human lung pairs were dissected into individual lungs and perfused on identical separate EVLP circuits, with one lung from each pair receiving a bolus of IL-1β. Fluorescently labeled human neutrophils isolated from a healthy volunteer were infused into both circuits and quantified in perfusate at regular timepoints. Perfusates and tissues were subsequently analyzed, with perfusates also used in functional assays. RESULTS Neutrophil numbers were significantly lower in perfusate samples collected from the IL-1β-stimulated lungs consistent with increased neutrophil adhesion ( P = 0.042). Stimulated lungs gained significantly more weight than controls ( P = 0.046), which correlated with soluble intercellular adhesion molecule-1 (R 2 = 0.71, P = 0.0043) and von-Willebrand factor (R 2 = 0.39, P = 0.040) in perfusate. RNA expression patterns for inflammatory genes were differentially regulated via IL-1β. Blockade of IL-1β significantly reduced neutrophil adhesion in vitro ( P = 0.025). CONCLUSION These data illustrate the proinflammatory functions of IL-1β in the context of EVLP, suggesting this pathway may be susceptible to therapeutic modulation before transplantation.
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Affiliation(s)
- Thomas Pither
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Lu Wang
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Lucy Bates
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Morvern Morrison
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Catriona Charlton
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Chelsea Griffiths
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Jamie Macdonald
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Venetia Bigley
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Maria Mavridou
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Joseph Barsby
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Lee Borthwick
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - John Dark
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - William Scott
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Simi Ali
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Andrew J Fisher
- Regenerative Medicine, Stem Cells and Transplantation Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
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23
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Peel JK, Pullenayegum EM, Naimark D, Aversa M, Liu M, Del Sorbo L, Barrett K, Sander B, Keshavjee S. Evaluating the Impact of Ex Vivo Lung Perfusion on Organ Transplantation: A Retrospective Cohort Study. Ann Surg 2023; 278:288-296. [PMID: 37073734 PMCID: PMC10321509 DOI: 10.1097/sla.0000000000005887] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2023]
Abstract
BACKGROUND Ex vivo lung perfusion (EVLP) sustains and allows advanced assessment of potentially useable donor lungs before transplantation, potentially relieving resource constraints. OBJECTIVE We sought to characterize the effect of EVLP on organ utilization and patient outcomes. METHODS We performed a retrospective, before-after cohort study using linked institutional data sources of adults wait-listed for lung transplant and donor organs transplanted in Ontario, Canada between 2005 and 2019. We regressed the annual number of transplants against year, EVLP use, and organ characteristics. Time-to-transplant, waitlist mortality, primary graft dysfunction, tracheostomy insertion, in-hospital mortality, and chronic lung allograft dysfunction were evaluated using propensity score-weighted regression. RESULTS EVLP availability ( P =0.01 for interaction) and EVLP use ( P <0.001 for interaction) were both associated with steeper increases in transplantation than expected by historical trends. EVLP was associated with more donation after circulatory death and extended-criteria donors transplanted, while the numbers of standard-criteria donors remained relatively stable. Significantly faster time-to-transplant was observed after EVLP was available (hazard ratio=1.64 [1.41-1.92]; P <0.001). Fewer patients died on the waitlist after EVLP was available, but no difference in the hazard of waitlist mortality was observed (HR=1.19 [0.81-1.74]; P =0.176). We observed no difference in the likelihood of chronic lung allograft dysfunction before versus after EVLP was available. CONCLUSIONS We observed a significant increase in organ transplantation since EVLP was introduced into practice, predominantly from increased acceptance of donation after circulatory death and extended-criteria lungs. Our findings suggest that EVLP-associated increases in organ availability meaningfully alleviated some barriers to transplant.
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Affiliation(s)
- John K. Peel
- Department of Anesthesiology, University Health Network, University of Toronto, Toronto, ON, Canada
- Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada
- Institute of Health Policy, Management and Evaluation, Dalla Lana School for Public Health, University of Toronto, Toronto, ON, Canada
| | - Eleanor M. Pullenayegum
- Institute of Health Policy, Management and Evaluation, Dalla Lana School for Public Health, University of Toronto, Toronto, ON, Canada
| | - David Naimark
- Institute of Health Policy, Management and Evaluation, Dalla Lana School for Public Health, University of Toronto, Toronto, ON, Canada
- Division of Nephrology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Meghan Aversa
- Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Mingyao Liu
- Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada
- Division of Thoracic Surgery, Toronto General Hospital, University Health Network
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Lorenzo Del Sorbo
- Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada
| | - Kali Barrett
- Institute of Health Policy, Management and Evaluation, Dalla Lana School for Public Health, University of Toronto, Toronto, ON, Canada
- Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada
| | - Beate Sander
- Institute of Health Policy, Management and Evaluation, Dalla Lana School for Public Health, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Institute for Clinical Evaluative Sciences, Toronto, ON, Canada
- Public Health Ontario, Toronto, ON, Canada
| | - Shaf Keshavjee
- Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada
- Division of Thoracic Surgery, Toronto General Hospital, University Health Network
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
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24
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Braithwaite SA, van Hooijdonk E, van der Kaaij NP. Ventilation during ex vivo lung perfusion, a review. Transplant Rev (Orlando) 2023; 37:100762. [PMID: 37099887 DOI: 10.1016/j.trre.2023.100762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 04/11/2023] [Accepted: 04/12/2023] [Indexed: 04/28/2023]
Abstract
Evidence suggests that ventilation during ex vivo lung perfusion (EVLP) with a 'one-size-fits-all' strategy has the potential to cause lung injury which may only become clinically relevant in marginal lung allografts. EVLP induced- or accelerated lung injury is a dynamic and cumulative process reflecting the interplay of a number of factors. Stress and strain in lung tissue caused by positive pressure ventilation may be exacerbated by the altered properties of lung tissue in an EVLP setting. Any pre-existing injury may alter the ability of lung allografts to accommodate set ventilation and perfusion techniques on EVLP leading to further injury. This review will examine the effects of ventilation on donor lungs in the setting of EVLP. A framework for developing a protective ventilation technique will be proposed.
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Affiliation(s)
- Sue A Braithwaite
- Department of Anesthesiology, University Medical Center Utrecht, Q04.2.317, Postbus 85500, Utrecht 3508, GA, the Netherlands.
| | - Elise van Hooijdonk
- Department of Cardiothoracic Surgery, University Medical Center Utrecht, Room E03.511, Heidelberglaan 100, Utrecht 3584, CX, the Netherlands
| | - Niels P van der Kaaij
- Department of Cardiothoracic Surgery, University Medical Center Utrecht, Room E03.511, Heidelberglaan 100, Utrecht 3584, CX, the Netherlands
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25
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Avtaar Singh SS, Das De S, Al-Adhami A, Singh R, Hopkins PMA, Curry PA. Primary graft dysfunction following lung transplantation: From pathogenesis to future frontiers. World J Transplant 2023; 13:58-85. [PMID: 36968136 PMCID: PMC10037231 DOI: 10.5500/wjt.v13.i3.58] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/11/2022] [Accepted: 02/17/2023] [Indexed: 03/16/2023] Open
Abstract
Lung transplantation is the treatment of choice for patients with end-stage lung disease. Currently, just under 5000 lung transplants are performed worldwide annually. However, a major scourge leading to 90-d and 1-year mortality remains primary graft dysfunction. It is a spectrum of lung injury ranging from mild to severe depending on the level of hypoxaemia and lung injury post-transplant. This review aims to provide an in-depth analysis of the epidemiology, patho physiology, risk factors, outcomes, and future frontiers involved in mitigating primary graft dysfunction. The current diagnostic criteria are examined alongside changes from the previous definition. We also highlight the issues surrounding chronic lung allograft dysfunction and identify the novel therapies available for ex-vivo lung perfusion. Although primary graft dysfunction remains a significant contributor to 90-d and 1-year mortality, ongoing research and development abreast with current technological advancements have shed some light on the issue in pursuit of future diagnostic and therapeutic tools.
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Affiliation(s)
- Sanjeet Singh Avtaar Singh
- Department of Cardiothoracic Surgery, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom
| | - Sudeep Das De
- Heart and Lung Transplant Unit, Wythenshawe Hospital, Manchester M23 9NJ, United Kingdom
| | - Ahmed Al-Adhami
- Department of Cardiothoracic Surgery, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
- Department of Heart and Lung Transplant, Royal Papworth Hospital, Cambridge CB2 0AY, United Kingdom
| | - Ramesh Singh
- Mechanical Circulatory Support, Inova Health System, Falls Church, VA 22042, United States
| | - Peter MA Hopkins
- Queensland Lung Transplant Service, Prince Charles Hospital, Brisbane, QLD 4032, Australia
| | - Philip Alan Curry
- Department of Cardiothoracic Surgery, Golden Jubilee National Hospital, Glasgow G81 4DY, United Kingdom
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26
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Peel JK, Keshavjee S, Naimark D, Liu M, Del Sorbo L, Cypel M, Barrett K, Pullenayegum EM, Sander B. Determining the impact of ex-vivo lung perfusion on hospital costs for lung transplantation: A retrospective cohort study. J Heart Lung Transplant 2023; 42:356-367. [PMID: 36411188 DOI: 10.1016/j.healun.2022.10.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 10/04/2022] [Accepted: 10/20/2022] [Indexed: 11/11/2022] Open
Abstract
INTRODUCTION Ex-vivo lung perfusion (EVLP) has improved organ utilization for lung transplantation, but it is not yet known whether the benefits of this technology offset its additional costs. We compared the institutional costs of lung transplantation before vs after EVLP was available to identify predictors of costs and determine the health-economic impact of EVLP. METHODS We performed a retrospective, before-after, propensity-score weighted cohort study of patients wait-listed for lung transplant at University Health Network (UHN) in Ontario, Canada, between January 2005 and December 2019 using institutional administrative data. We compared costs, in 2019 Canadian Dollars ($), between patients referred for transplant before EVLP was available (Pre-EVLP) to after (Modern EVLP). Cumulative costs were estimated using a novel application of multistate survival models. Predictors of costs were identified using weighted log-gamma generalized linear regression. RESULTS A total of 1,199 patients met inclusion criteria (352 Pre-EVLP; 847 Modern EVLP). Mean total costs for the transplant hospitalization were $111,878 ($94,123-$130,767) in the Pre-EVLP era and $110,969 ($87,714-$136,000) in the Modern EVLP era. Cumulative five-year costs since referral were $278,777 ($82,575-$298,135) in the Pre-EVLP era and $293,680 ($252,832-$317,599) in the Modern EVLP era. We observed faster progression to transplantation when EVLP was available. EVLP availability was not a predictor of waitlist (cost ratio [CR] 1.04 [0.81-1.37]; p = 0.354) or transplant costs (CR 1.02 [0.80-1.29]; p = 0.425) but was associated with lower costs during posttransplant years 1&2 (CR 0.75 [0.58-1.06]; p = 0.05) and posttransplant years 3+ (CR 0.43 [0.26-0.74]; p = 0.001). CONCLUSIONS At our center, EVLP availability was associated with faster progression to transplantation at no significant marginal cost.
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Affiliation(s)
- John Kenneth Peel
- Department of Anesthesiology, University Health Network, Toronto, Ontario, Canada; Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, Dalla Lana School for Public Health, University of Toronto, Toronto, Ontario, Canada.
| | - Shaf Keshavjee
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada; Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - David Naimark
- Institute of Health Policy, Management and Evaluation, Dalla Lana School for Public Health, University of Toronto, Toronto, Ontario, Canada; Division of Nephrology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Mingyao Liu
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada; Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Lorenzo Del Sorbo
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Marcelo Cypel
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada; Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Kali Barrett
- Institute of Health Policy, Management and Evaluation, Dalla Lana School for Public Health, University of Toronto, Toronto, Ontario, Canada; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Eleanor M Pullenayegum
- Institute of Health Policy, Management and Evaluation, Dalla Lana School for Public Health, University of Toronto, Toronto, Ontario, Canada; The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Beate Sander
- Institute of Health Policy, Management and Evaluation, Dalla Lana School for Public Health, University of Toronto, Toronto, Ontario, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; ICES, Ontario, Canada; Public Health Ontario, Ontario, Canada.
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27
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Diagnostic and Therapeutic Implications of Ex Vivo Lung Perfusion in Lung Transplantation: Potential Benefits and Inherent Limitations. Transplantation 2023; 107:105-116. [PMID: 36508647 DOI: 10.1097/tp.0000000000004414] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ex vivo lung perfusion (EVLP), a technique in which isolated lungs are continually ventilated and perfused at normothermic temperature, is emerging as a promising platform to optimize donor lung quality and increase the lung graft pool. Over the past few decades, the EVLP technique has become recognized as a significant achievement and gained much attention in the field of lung transplantation. EVLP has been demonstrated to be an effective platform for various targeted therapies to optimize donor lung function before transplantation. Additionally, some physical parameters during EVLP and biological markers in the EVLP perfusate can be used to evaluate graft function before transplantation and predict posttransplant outcomes. However, despite its advantages, the clinical practice of EVLP continuously encounters multiple challenges associated with both intrinsic and extrinsic limitations. It is of utmost importance to address the advantages and disadvantages of EVLP for its broader clinical usage. Here, the pros and cons of EVLP are comprehensively discussed, with a focus on its benefits and potential approaches for overcoming the remaining limitations. Directions for future research to fully explore the clinical potential of EVLP in lung transplantation are also discussed.
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28
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Remote ex vivo lung perfusion at a centralized evaluation facility. J Heart Lung Transplant 2022; 41:1700-1711. [PMID: 36229329 DOI: 10.1016/j.healun.2022.09.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 08/24/2022] [Accepted: 09/08/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND In the US, only 23% of lungs offered for transplantation are transplanted. Ex vivo lung perfusion (EVLP) allows for evaluation of additional donor lungs; its adoption has been limited by resources and expertise. Dedicated facilities with a centralized lung evaluation system (CLES) could expand access to EVLP. METHODS In this unblinded, nonrandomized, traditional feasibility study, 7 US transplant centers referred lungs declined for standard transplantation to a dedicated EVLP facility, which utilized a CLES. EVLP was remotely monitored by the transplant teams. CLES lungs were matched with contemporaneous conventional static cold-preserved controls at each center. RESULTS A total of 115 recipients were enrolled, and 66 received allografts from 63 donors after EVLP at the dedicated CLES facility. Forty-nine contemporaneous patients served as controls. Primary graft dysfunction grade 3 at 72 hours (PGD3-72 hours) was higher in the CLES group with 16 (24%) vs 2 (4%) in the control (common RD 95% CI, 0.07-0.32; p = 0.0009). All recipients survived to 30 days and 1-year survival was similar for both groups (92% controls vs 89% CLES; common RD 95% CI, -0.14-0.08; p = 0.58). Total preservation time, hospital and ICU lengths of stay, and time to first extubation were longer in the CLES group. CONCLUSIONS Remote ex vivo perfusion of lung allografts declined for conventional transplantation at a dedicated CLES facility is feasible and resulted in additional transplants. Recipients of allografts assessed with a CLES had a higher rate of PGD3-72 hours, but similar 30-day and 1-year outcomes compared to conventional lung recipients. (NCT02234128).
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29
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Roesel MJ, Wiegmann B, Ius F, Knosalla C, Iske J. The role of ex-situ perfusion for thoracic organs. Curr Opin Organ Transplant 2022; 27:466-473. [PMID: 35950888 DOI: 10.1097/mot.0000000000001008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE OF REVIEW Ex-situ machine perfusion for both heart (HTx) and lung transplantation (LuTx) reduces ischemia-reperfusion injury (IRI), allows for greater flexibility in geographical donor management, continuous monitoring, organ assessment for extended evaluation, and potential reconditioning of marginal organs. In this review, we will delineate the impact of machine perfusion, characterize novel opportunities, and outline potential challenges lying ahead to improve further implementation. RECENT FINDINGS Due to the success of several randomized controlled trials (RCT), comparing cold storage to machine perfusion in HTx and LuTx, implementation and innovation continues. Indeed, it represents a promising interface for organ-specific therapies targeting IRI, allo-immune responses, and graft reconditioning. These mostly experimental efforts range from genetic approaches and nanotechnology to cellular therapies, involving mesenchymal stem cell application. Despite tremendous potential, prior to clinical transition, more data is needed. SUMMARY Collectively, machine perfusion constitutes the vanguard in thoracic organ transplantation research with extensive potential for expanding the donor pool, enhancing transplant outcomes as well as developing novel therapy approaches.
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Affiliation(s)
- Maximilian J Roesel
- Department of Cardiothoracic Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany
- Institute of Medical Immunology, Charite Universitaetsmedizin Berlin, Berlin, Germany
| | - Bettina Wiegmann
- Department for Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
- German Center for Lung Research (DZL), Hannover, Germany
- DFG Priority Program SPP 2014, German Research Foundation, Bonn, Germany
| | - Fabio Ius
- Department for Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Christoph Knosalla
- Department of Cardiothoracic Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany
| | - Jasper Iske
- Department of Cardiothoracic Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany
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30
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Miller CL, O JM, Allan JS, Madsen JC. Novel approaches for long-term lung transplant survival. Front Immunol 2022; 13:931251. [PMID: 35967365 PMCID: PMC9363671 DOI: 10.3389/fimmu.2022.931251] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/04/2022] [Indexed: 11/16/2022] Open
Abstract
Allograft failure remains a major barrier in the field of lung transplantation and results primarily from acute and chronic rejection. To date, standard-of-care immunosuppressive regimens have proven unsuccessful in achieving acceptable long-term graft and patient survival. Recent insights into the unique immunologic properties of lung allografts provide an opportunity to develop more effective immunosuppressive strategies. Here we describe advances in our understanding of the mechanisms driving lung allograft rejection and highlight recent progress in the development of novel, lung-specific strategies aimed at promoting long-term allograft survival, including tolerance.
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Affiliation(s)
- Cynthia L. Miller
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States
| | - Jane M. O
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States
| | - James S. Allan
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States
- Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, United States
| | - Joren C. Madsen
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States
- Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, United States
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31
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Hirdman G, Niroomand A, Olm F, Lindstedt S. Taking a Deep Breath: an Examination of Current Controversies in Surgical Procedures in Lung Transplantation. CURRENT TRANSPLANTATION REPORTS 2022; 9:160-172. [PMID: 35601346 PMCID: PMC9108015 DOI: 10.1007/s40472-022-00367-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2022] [Indexed: 11/30/2022]
Abstract
Purpose of Review This article reviews controversial questions within the field of lung transplantation, with a focus on data generated within the last 3 years. We aim to summarize differing opinions on a selection of topics, including bridge-to-transplantation, intraoperative machine circulatory support, bronchial anastomosis, size mismatch, delayed chest closure, and ex vivo lung perfusion. Recent Findings With the growing rate of lung transplantations worldwide and increasing numbers of patients placed on waiting lists, the importance of determining best practices has only increased in recent years. Factors which promote successful outcomes have been identified across all the topics, with certain approaches promoted, such as ambulation in bridge-to-transplant and widespread intraoperative ECMO as machine support. Summary While great strides have been made in the operative procedures involved in lung transplantation, there are still key questions to be answered. The consensus which can be reached will be instrumental in further improving outcomes in recipients.
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Affiliation(s)
- Gabriel Hirdman
- Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital, Lund University, Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Anna Niroomand
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
- Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ USA
| | - Franziska Olm
- Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital, Lund University, Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Sandra Lindstedt
- Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital, Lund University, Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
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32
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Abdoul N, Legeai C, Cantrelle C, Mercier O, Olland A, Mordant P, Thomas PA, Jougon J, Tissot A, Maury JM, Sage E, Dorent R. Impact of ex vivo lung perfusion on brain-dead donor lung utilization: The French experience. Am J Transplant 2022; 22:1409-1417. [PMID: 35000283 DOI: 10.1111/ajt.16953] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/17/2021] [Accepted: 01/04/2022] [Indexed: 01/25/2023]
Abstract
Ex vivo lung perfusion (EVLP) is a valuable method for expanding the lung donor pool. Its indications currently differ across centers. This national retrospective cohort study aimed to describe the profile of donors with lungs transplanted after EVLP and determine the effectiveness of EVLP on lung utilization. We included brain-dead donors with at least one lung offered between 2012 and 2019 in France. Lungs transplanted without or after EVLP were compared with those that were rejected. Donor group phenotypes were determined with multiple correspondence analysis (MCA). The association between donor factors and lung transplantation was assessed with a multivariable multinomial logistic regression. MCA revealed that donors whose lungs were transplanted after EVLP had profiles similar to the donors whose lungs were declined and quite different from those of donors with lungs transplanted without EVLP. Donor predictors of graft nonuse included age ≥50 years, smoking history, PaO2 /FiO2 ratio ≤300 mmHg, abnormal chest imaging, and purulent secretions. EVLP increased utilization of lungs from donors with a smoking history, PaO2 /FiO2 ratio ≤300 mmHg, and abnormal chest imaging.
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Affiliation(s)
| | | | | | - Olaf Mercier
- Department of Thoracic Surgery and Lung Transplantation, Marie Lannelongue Hospital, Le Plessis Robinson, France
| | - Anne Olland
- Department of Thoracic Surgery, University Hospital Strasbourg, Strasbourg, France
| | - Pierre Mordant
- Division of Thoracic and Vascular Surgery, Bichat Hospital, Assistance Publique-Hôpitaux de Paris, Paris University, Paris, France
| | | | - Jacques Jougon
- Department of Thoracic Surgery, Haut-Leveque Hospital, Bordeaux University, Bordeaux, France
| | - Adrien Tissot
- Department of Pneumology, Thorax Institute, Nantes University Hospital, Nantes, France
| | - Jean-Michel Maury
- Department of Thoracic Surgery, Lung and Lung Transplantation, Louis Pradel Hospital, Lyon, France
| | - Edouard Sage
- Department of Thoracic Surgery and Lung Transplantation, Foch Hospital, Suresnes, France
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Lee ACH, Edobor A, Wigakumar T, Lysandrou M, Johnston LK, McMullen P, Mirle V, Diaz A, Piech R, Rose R, Jendrisak M, di Sabato D, Shanmugarajah K, Fung J, Donington J, Madariaga ML. Donor leukocyte trafficking during human ex vivo lung perfusion. Clin Transplant 2022; 36:e14670. [PMID: 35396887 PMCID: PMC9540615 DOI: 10.1111/ctr.14670] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 03/09/2022] [Accepted: 04/04/2022] [Indexed: 11/30/2022]
Abstract
Background Ex vivo lung perfusion (EVLP) is used to assess and preserve lungs prior to transplantation. However, its inherent immunomodulatory effects are not completely understood. We examine perfusate and tissue compartments to determine the change in immune cell composition in human lungs maintained on EVLP. Methods Six human lungs unsuitable for transplantation underwent EVLP. Tissue and perfusate samples were obtained during cold storage and at 1‐, 3‐ and 6‐h during perfusion. Flow cytometry, immunohistochemistry, and bead‐based immunoassays were used to measure leukocyte composition and cytokines. Mean values between baseline and time points were compared by Student's t test. Results During the 1st hour of perfusion, perfusate neutrophils increased (+22.2 ± 13.5%, p < 0.05), monocytes decreased (−77.5 ± 8.6%, p < 0.01) and NK cells decreased (−61.5 ± 22.6%, p < 0.01) compared to cold storage. In contrast, tissue neutrophils decreased (−22.1 ± 12.2%, p < 0.05) with no change in monocytes and NK cells. By 6 h, perfusate neutrophils, NK cells, and tissue neutrophils were similar to baseline. Perfusate monocytes remained decreased, while tissue monocytes remained unchanged. There was no significant change in B cells or T cell subsets. Pro‐inflammatory cytokines (IL‐1b, G‐CSF, IFN‐gamma, CXCL2, CXCL1 granzyme A, and granzyme B) and lymphocyte activating cytokines (IL‐2, IL‐4, IL‐6, IL‐8) increased during perfusion. Conclusions Early mobilization of innate immune cells occurs in both perfusate and tissue compartments during EVLP, with neutrophils and NK cells returning to baseline and monocytes remaining depleted after 6 h. The immunomodulatory effect of EVLP may provide a therapeutic window to decrease the immunogenicity of lungs prior to transplantation.
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Affiliation(s)
| | - Arianna Edobor
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | | | - Maria Lysandrou
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | - Laura K Johnston
- Office of Shared Research Facilities, University of Chicago, Chicago, Illinois, USA
| | - Phillip McMullen
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
| | - Vikranth Mirle
- Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Ashley Diaz
- Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Ryan Piech
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | - Rebecca Rose
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | | | - Diego di Sabato
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | | | - John Fung
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | - Jessica Donington
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
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Ex Vivo Lung Perfusion: A Review of Current and Future Application in Lung Transplantation. Pulm Ther 2022; 8:149-165. [PMID: 35316525 PMCID: PMC9098710 DOI: 10.1007/s41030-022-00185-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 01/25/2022] [Indexed: 12/23/2022] Open
Abstract
The number of waitlisted lung transplant candidates exceeds the availability of donor organs. Barriers to utilization of donor lungs include suboptimal lung allograft function, long ischemic times due to geographical distance between donor and recipient, and a wide array of other logistical and medical challenges. Ex vivo lung perfusion (EVLP) is a modality that allows donor lungs to be evaluated in a closed circuit outside of the body and extends lung donor assessment prior to final acceptance for transplantation. EVLP was first utilized successfully in 2001 in Lund, Sweden. Since its initial use, EVLP has facilitated hundreds of lung transplants that would not have otherwise happened. EVLP technology continues to evolve and improve, and currently there are multiple commercially available systems, and more under investigation worldwide. Although barriers to universal utilization of EVLP exist, the possibility for more widespread adaptation of this technology abounds. Not only does EVLP have diagnostic capabilities as an organ monitoring device but also the therapeutic potential to improve lung allograft quality when specific issues are encountered. Expanded treatment potential includes the use of immunomodulatory treatment to reduce primary graft dysfunction, as well as targeted antimicrobial therapy to treat infection. In this review, we will highlight the historical development, the current state of utilization/capability, and the future promise of this technology.
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Stefanuto PH, Romano R, Rees CA, Nasir M, Thakuria L, Simon A, Reed AK, Marczin N, Hill JE. Volatile organic compound profiling to explore primary graft dysfunction after lung transplantation. Sci Rep 2022; 12:2053. [PMID: 35136125 PMCID: PMC8827074 DOI: 10.1038/s41598-022-05994-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 11/29/2021] [Indexed: 01/07/2023] Open
Abstract
Primary graft dysfunction (PGD) is a major determinant of morbidity and mortality following lung transplantation. Delineating basic mechanisms and molecular signatures of PGD remain a fundamental challenge. This pilot study examines if the pulmonary volatile organic compound (VOC) spectrum relate to PGD and postoperative outcomes. The VOC profiles of 58 bronchoalveolar lavage fluid (BALF) and blind bronchial aspirate samples from 35 transplant patients were extracted using solid-phase-microextraction and analyzed with comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry. The support vector machine algorithm was used to identify VOCs that could differentiate patients with severe from lower grade PGD. Using 20 statistically significant VOCs from the sample headspace collected immediately after transplantation (< 6 h), severe PGD was differentiable from low PGD with an AUROC of 0.90 and an accuracy of 0.83 on test set samples. The model was somewhat effective for later time points with an AUROC of 0.80. Three major chemical classes in the model were dominated by alkylated hydrocarbons, linear hydrocarbons, and aldehydes in severe PGD samples. These VOCs may have important clinical and mechanistic implications, therefore large-scale study and potential translation to breath analysis is recommended.
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Affiliation(s)
- Pierre-Hugues Stefanuto
- Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.,Organic and Biological Analytical Chemistry Group, Liège University, Liège, Belgium
| | - Rosalba Romano
- Department of Surgery and Cancer, Section of Anaesthetics, Imperial College of London, London, UK.,Harefield Hospital, Royal Brompton and Harefield NHS Foundation Trust, Harefield, UK
| | | | - Mavra Nasir
- Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Louit Thakuria
- Harefield Hospital, Royal Brompton and Harefield NHS Foundation Trust, Harefield, UK
| | - Andre Simon
- Harefield Hospital, Royal Brompton and Harefield NHS Foundation Trust, Harefield, UK
| | - Anna K Reed
- Harefield Hospital, Royal Brompton and Harefield NHS Foundation Trust, Harefield, UK
| | - Nandor Marczin
- Department of Surgery and Cancer, Section of Anaesthetics, Imperial College of London, London, UK.,Harefield Hospital, Royal Brompton and Harefield NHS Foundation Trust, Harefield, UK.,Department of Anesthesia and Intensive Care, Semmelweis University, Budapest, Hungary
| | - Jane E Hill
- Thayer School of Engineering, Dartmouth College, Hanover, NH, USA. .,Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. .,Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, Canada.
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36
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Ex-vivo lung perfusion therapies. Curr Opin Organ Transplant 2022; 27:204-210. [DOI: 10.1097/mot.0000000000000961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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Samchuk O, Matolinets N, Miskiv I, Orlynska K, Gumennyi I. FIRST BILATERAL LUNG TRANSPLANTATION VIA ANTEROLATERAL THORACOTOMY IN UKRAINE. WIADOMOSCI LEKARSKIE (WARSAW, POLAND : 1960) 2022; 75:1403-1407. [PMID: 35758465 DOI: 10.36740/wlek202205230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
OBJECTIVE The aim: The aim of this work is to describe the clinical case of the first lung transplant in Ukraine through anterolateral access and to analyze management of patient in the postoperative period, followed by assessment of his general condition and quality of life. PATIENTS AND METHODS Materials and methods: Analysis of the clinical case of the patient who underwent the first lung transplantation in Ukraine, including a description of surgery, anesthesia, and postoperative recovery. CONCLUSION Conclusions: Thus, based on the data of the world literature, as well as on the results of treatment on the basis of Municipal Non-Profit Enterprise " Lviv Emergency Clinical Hospital" we can conclude that lung transplantation is one of the most effective methods of treatment of patients with end-stage lung disease. This operation improves patients' quality of life, general well-being and ability to physical activity.
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Affiliation(s)
- Oleg Samchuk
- LVIV TERRITORIAL MEDICAL GROUP "MULTIDISCIPLINARY CLINICAL HOSPITAL OF INTENSIVE CARE AND EMERGENCY", LVIV, UKRAINE
| | - Nataliya Matolinets
- LVIV TERRITORIAL MEDICAL GROUP "MULTIDISCIPLINARY CLINICAL HOSPITAL OF INTENSIVE CARE AND EMERGENCY", LVIV, UKRAINE
| | - Ivan Miskiv
- LVIV TERRITORIAL MEDICAL GROUP "MULTIDISCIPLINARY CLINICAL HOSPITAL OF INTENSIVE CARE AND EMERGENCY", LVIV, UKRAINE
| | - Khrystyna Orlynska
- LVIV TERRITORIAL MEDICAL GROUP "MULTIDISCIPLINARY CLINICAL HOSPITAL OF INTENSIVE CARE AND EMERGENCY", LVIV, UKRAINE
| | - Igor Gumennyi
- LVIV TERRITORIAL MEDICAL GROUP "MULTIDISCIPLINARY CLINICAL HOSPITAL OF INTENSIVE CARE AND EMERGENCY", LVIV, UKRAINE
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Ferdinand JR, Morrison MI, Andreasson A, Charlton C, Chhatwal AK, Scott WE, Borthwick LA, Clatworthy MR, Fisher AJ. Transcriptional analysis identifies potential novel biomarkers associated with successful ex-vivo perfusion of human donor lungs. Clin Transplant 2021; 36:e14570. [PMID: 34954872 PMCID: PMC9285052 DOI: 10.1111/ctr.14570] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 12/14/2021] [Accepted: 12/20/2021] [Indexed: 11/30/2022]
Abstract
Background Transplantation is an effective treatment for end‐stage lung disease, but the donor organ shortage is a major problem. Ex‐vivo lung perfusion (EVLP) of extended criteria organs enables functional assessment to facilitate clinical decision‐making around utilization, but the molecular processes occurring during EVLP, and how they differ between more or less viable lungs, remain to be determined. Methods We used RNA sequencing of lung tissue to delineate changes in gene expression occurring in 10 donor lungs undergoing EVLP and compare lungs that were deemed non‐transplantable (n = 4) to those deemed transplantable (n = 6) following perfusion. Results We found that lungs deemed unsuitable for transplantation had increased induction of innate immune pathways and lower expression of oxidative phosphorylation related genes. Furthermore, the expression of SCGB1A1, a gene encoding an anti‐inflammatory secretoglobin CC10, and other club cell genes was significantly decreased in non‐transplantable lungs, while CHIT‐1 was increased. Using a larger validation cohort (n = 17), we confirmed that the ratio of CHIT1 and SCGB1A1 protein levels in lung perfusate have potential utility to distinguish transplantable from non‐transplantable lungs (AUC .81). Conclusions Together, our data identify novel biomarkers that may assist with pre‐transplant lung assessment, as well as pathways that may be amenable to therapeutic intervention during EVLPAQ6.
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Affiliation(s)
- John Robert Ferdinand
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK
| | | | - Anders Andreasson
- Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne, UK
| | - Catriona Charlton
- Newcastle University Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, UK
| | - Alisha Kaur Chhatwal
- Newcastle University Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, UK
| | - William Earl Scott
- Newcastle University Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, UK
| | - Lee Anthony Borthwick
- Newcastle University Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, UK
| | - Menna Ruth Clatworthy
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK.,Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK
| | - Andrew J Fisher
- Newcastle University Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, UK.,Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne, UK
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Iske J, Hinze CA, Salman J, Haverich A, Tullius SG, Ius F. The potential of ex vivo lung perfusion on improving organ quality and ameliorating ischemia reperfusion injury. Am J Transplant 2021; 21:3831-3839. [PMID: 34355495 PMCID: PMC8925042 DOI: 10.1111/ajt.16784] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/02/2021] [Accepted: 08/03/2021] [Indexed: 01/25/2023]
Abstract
Allogeneic lung transplantation (LuTx) is considered the treatment of choice for a broad range of advanced, progressive lung diseases resistant to conventional treatment regimens. Ischemia reperfusion injury (IRI) occurring upon reperfusion of the explanted, ischemic lung during implantation remains a crucial mediator of primary graft dysfunction (PGD) and early allo-immune responses. Ex vivo lung perfusion (EVLP) displays an advanced technique aiming at improving lung procurement and preservation. Indeed, previous clinical trials have demonstrated a reduced incidence of PGD following LuTx utilizing EVLP, while long-term outcomes are yet to be evaluated. Mechanistically, EVLP may alleviate donor lung inflammation through reconditioning the injured lung and diminishing IRI through storing the explanted lung in a non-ischemic, perfused, and ventilated status. In this work, we review potential mechanisms of EVLP that may attenuate IRI and improve organ quality. Moreover, we dissect experimental treatment approaches during EVLP that may further attenuate inflammatory events deriving from tissue ischemia, shear forces or allograft rejection associated with LuTx.
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Affiliation(s)
- Jasper Iske
- Department of Cardiothoracic-, Transplant, and Vascular Surgery, Hannover Medical School, Hannover, Lower Saxony, Germany.,Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Christopher A. Hinze
- Department of Cardiothoracic-, Transplant, and Vascular Surgery, Hannover Medical School, Hannover, Lower Saxony, Germany
| | - Jawad Salman
- Department of Cardiothoracic-, Transplant, and Vascular Surgery, Hannover Medical School, Hannover, Lower Saxony, Germany
| | - Axel Haverich
- Department of Cardiothoracic-, Transplant, and Vascular Surgery, Hannover Medical School, Hannover, Lower Saxony, Germany.,Biomedical research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany
| | - Stefan G. Tullius
- Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Fabio Ius
- Department of Cardiothoracic-, Transplant, and Vascular Surgery, Hannover Medical School, Hannover, Lower Saxony, Germany.,Biomedical research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany.,Correspondence: Fabio Ius, MD, Department of Heart-, Thoracic-, Vascular-, and Transplant Surgery, Hannover Medical School, 1 Carl-Neuberg-Street, 30625 Hannover, Germany, Tel: +49 511 532 2125, Fax: +49 511 532 8436,
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40
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Peel JK, Keshavjee S, Krahn M, Sander B. Economic evaluations and costing studies of lung transplantation: A scoping review. J Heart Lung Transplant 2021; 40:1625-1640. [PMID: 34538540 DOI: 10.1016/j.healun.2021.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 07/31/2021] [Accepted: 08/19/2021] [Indexed: 10/20/2022] Open
Abstract
BACKGROUND Evaluation of the joint clinical and economic impacts of lung transplant and associated technologies is crucial for evidence-informed decision-making and wise allocation of scarce healthcare resources. We performed a scoping review to summarize and categorize the available evidence of the costs and cost-effectiveness of lung transplantation. METHODS A systematic search of MEDLINE, EMBASE, NHS EED, and EconLit was performed to identify studies involving lung transplantation for adults that measured costs, cost-effectiveness, or which described themselves as economic evaluations. A scoping review was performed in adherence to the framework described by Arksey & O'Malley. Risk of bias was assessed in included studies using the ECOBIAS and CHEC-list tools. RESULTS In total, 324 studies were identified, of which 28 met inclusion criteria. Cost-utility estimates of lung transplant versus waitlist, from the healthcare payer perspective and a time-horizon of at least 10-years ranged between $42,459 and $154,051 per quality-adjusted life year. Common topics of study included lung transplant versus waitlist care, immunosuppression, organ retrieval and allocation, and mechanical life support. CONCLUSIONS Sources of variation in costs-assessments and economic evaluations included differences in the type of study performed, payer perspective adopted, study time horizon, and variation in clinical practice. The best available cost-utility estimates for lung transplant versus waitlist may represent cost-effectiveness under some circumstances, but high-quality evidence is lacking. Further cost-utility analyses, with sufficient methodologic rigour, are required to overcome the observed variation in results and confirm cost-effectiveness of the current standard of care in lung transplantation.
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Affiliation(s)
- J K Peel
- Department of Anesthesiology & Pain Medicine, University of Toronto, ON, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, ON, Canada; Toronto Health Economics and Technology Assessment Collaborative, Toronto, ON, Canada.
| | - S Keshavjee
- Division of Thoracic Surgery, Toronto General Hospital, University Health Network, ON, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - M Krahn
- Institute of Health Policy, Management and Evaluation, University of Toronto, ON, Canada; Toronto Health Economics and Technology Assessment Collaborative, Toronto, ON, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Department of Medicine, University Health Network, Toronto, ON, Canada
| | - B Sander
- Institute of Health Policy, Management and Evaluation, University of Toronto, ON, Canada; Toronto Health Economics and Technology Assessment Collaborative, Toronto, ON, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; Department of Medicine, University Health Network, Toronto, ON, Canada
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41
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Di Nardo M, Del Sorbo L, Sage A, Ma J, Liu M, Yeung JC, Valero J, Ghany R, Cypel M, Keshavjee S. Predicting donor lung acceptance for transplant during ex vivo lung perfusion: The EX vivo lung PerfusIon pREdiction (EXPIRE). Am J Transplant 2021; 21:3704-3713. [PMID: 33872459 DOI: 10.1111/ajt.16616] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/11/2021] [Accepted: 04/12/2021] [Indexed: 01/25/2023]
Abstract
Ex vivo lung perfusion (EVLP) has being increasingly used for the pretransplant assessment of extended-criteria donor lungs. Mathematical models to predict lung acceptance during EVLP have not been reported so far. Thus, we hypothesized that predictors of lung acceptance could be identified and used to develop a mathematical model describing the clinical decision-making process used in our institution. Donor lungs characteristics and EVLP physiologic parameters included in our EVLP registry were examined (derivation cohort). Multivariable logistic regression analysis was performed to identify predictors independently associated with lung acceptance. A mathematical model (EX vivo lung PerfusIon pREdiction [EXPIRE] model) for each hour of EVLP was developed and validated using a new cohort (validation cohort). Two hundred eighty donor lungs were assessed with EVLP. Of these, 186 (66%) were accepted for transplantation. ΔPO2 and static compliance/total lung capacity were identified as independent predictors of lung acceptance and their respective cut-off values were determined. The EXPIRE model showed a low discriminative power at the first hour of EVLP assessment (AUC: 0.69 [95% CI: 0.62-0.77]), which progressively improved up to the fourth hour (AUC: 0.87 [95% CI: 0.83-0.92]). In a validation cohort, the EXPIRE model demonstrated good discriminative power, peaking at the fourth hour (AUC: 0.85 [95% CI: 0.76-0.94]). The EXPIRE model may help to standardize lung assessment in centers using the Toronto EVLP technique and improve overall transplant rates.
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Affiliation(s)
- Matteo Di Nardo
- Pediatric Intensive Care Unit, Bambino Gesù, Children's Hospital, IRCCS, Rome, Italy.,Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, University Health Network, Toronto, ON, Canada
| | - Lorenzo Del Sorbo
- Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, University Health Network, Toronto, ON, Canada.,Interdepartmental Division of Critical Care Medicine, Medical and Surgical Intensive Care Unit, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Andrew Sage
- Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, University Health Network, Toronto, ON, Canada
| | - Jin Ma
- Biostatistics Research Unit, University Health Network, Toronto, ON, Canada
| | - Mingyao Liu
- Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, University Health Network, Toronto, ON, Canada.,Multiorgan Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada.,Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Jonathan C Yeung
- Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, University Health Network, Toronto, ON, Canada.,Multiorgan Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada.,Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Jerome Valero
- Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, University Health Network, Toronto, ON, Canada
| | - Rasheed Ghany
- Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, University Health Network, Toronto, ON, Canada
| | - Marcelo Cypel
- Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, University Health Network, Toronto, ON, Canada.,Multiorgan Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada.,Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Shaf Keshavjee
- Latner Thoracic Research Laboratories, Toronto Lung Transplant Program, University Health Network, Toronto, ON, Canada.,Multiorgan Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada.,Institute of Medical Science, University of Toronto, Toronto, ON, Canada
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REBOARREST, resuscitative endovascular balloon occlusion of the aorta in non-traumatic out-of-hospital cardiac arrest: a study protocol for a randomised, parallel group, clinical multicentre trial. Trials 2021; 22:511. [PMID: 34332617 PMCID: PMC8325811 DOI: 10.1186/s13063-021-05477-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/20/2021] [Indexed: 11/24/2022] Open
Abstract
Background Survival after out-of-hospital cardiac arrest (OHCA) is poor and dependent on high-quality cardiopulmonary resuscitation. Resuscitative endovascular balloon occlusion of the aorta (REBOA) may be advantageous in non-traumatic OHCA due to the potential benefit of redistributing the cardiac output to organs proximal to the aortic occlusion. This theory is supported by data from both preclinical studies and human case reports. Methods This multicentre trial will enrol 200 adult patients, who will be randomised in a 1:1 ratio to either a control group that receives advanced cardiovascular life support (ACLS) or an intervention group that receives ACLS and REBOA. The primary endpoint will be the proportion of patients who achieve return of spontaneous circulation with a duration of at least 20 min. The secondary objectives of this trial are to measure the proportion of patients surviving to 30 days with good neurological status, to describe the haemodynamic physiology of aortic occlusion during ACLS, and to document adverse events. Discussion Results from this study will assess the efficacy and safety of REBOA as an adjunctive treatment for non-traumatic OHCA. This novel use of REBOA may contribute to improve treatment for this patient cohort. Trial registration The trial is approved by the Regional Committee for Medical and Health Research Ethics in Norway (reference 152504) and is registered at ClinicalTrials.gov (reference NCT04596514) and as Universal Trial Number WHO: U1111-1253-0322. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-021-05477-1.
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Pro-IL-1β Is an Early Prognostic Indicator of Severe Donor Lung Injury During Ex Vivo Lung Perfusion. Transplantation 2021; 105:768-774. [PMID: 32976365 DOI: 10.1097/tp.0000000000003463] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Ex vivo lung perfusion (EVLP) is used to evaluate and recondition extended criteria donor lungs for transplantation. Interleukin-1β (IL-1β) has been identified as a prognostic indicator of nonrecovery during EVLP. This may be an effect of inflammasome activation or cellular necrosis following donation and graft preservation. Delineating the mechanism of IL-1β release is required. METHODS The inactive intracellular precursor molecule, pro-IL-1β, was characterized along with the pro-IL-1β processing enzyme, caspase-1, in the perfusate of n = 20 human lungs that had undergone EVLP (n = 10 lungs that failed to recover and were discarded versus n = 10 lungs that reconditioned and were transplanted). In an experimental porcine model, n = 8 lungs underwent EVLP and were randomized to receive either a specific NLRP3 inflammasome inhibitor or control. RESULTS Significant increases in pro-IL-1β and caspase-1 were observed in the perfusate from human lungs that did not recondition during EVLP compared with those that successfully reconditioned and were used for transplantation. Within the porcine EVLP, NLRP3 inflammasome inhibition reduced IL-1β within the perfusate compared with controls, but this had no impact on lung function, hemodynamics, or inflammation. CONCLUSIONS Our data suggest that pro-IL-1β is passively released following cellular necrosis of the donor lung.
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Piechura LM, Rinewalt DE, Mallidi HR. Advanced Surgical and Percutaneous Approaches to Pulmonary Vascular Disease. Clin Chest Med 2021; 42:143-154. [PMID: 33541608 DOI: 10.1016/j.ccm.2020.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Despite progress in modern medical therapy, pulmonary hypertension remains an unremitting disease. Once severe or refractory to medical therapy, advanced percutaneous and surgical interventions can palliate right ventricular overload, bridge to transplantation, and overall extend a patient's course. These approaches include atrial septostomy, Potts shunt, and extracorporeal life support. Bilateral lung transplantation is the ultimate treatment for eligible patients, although the need for suitable lungs continues to outpace availability. Measures such as ex vivo lung perfusion are ongoing to expand donor lung availability, increase rates of transplant, and decrease waitlist mortality.
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Affiliation(s)
- Laura M Piechura
- Division of Cardiac Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; Division of Thoracic Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Daniel E Rinewalt
- Division of Cardiac Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Hari R Mallidi
- Division of Cardiac Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; Division of Thoracic Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
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Lung Transplantation, Pulmonary Endothelial Inflammation, and Ex-Situ Lung Perfusion: A Review. Cells 2021; 10:cells10061417. [PMID: 34200413 PMCID: PMC8229792 DOI: 10.3390/cells10061417] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/01/2021] [Accepted: 06/02/2021] [Indexed: 12/31/2022] Open
Abstract
Lung transplantation (LTx) is the gold standard treatment for end-stage lung disease; however, waitlist mortality remains high due to a shortage of suitable donor lungs. Organ quality can be compromised by lung ischemic reperfusion injury (LIRI). LIRI causes pulmonary endothelial inflammation and may lead to primary graft dysfunction (PGD). PGD is a significant cause of morbidity and mortality post-LTx. Research into preservation strategies that decrease the risk of LIRI and PGD is needed, and ex-situ lung perfusion (ESLP) is the foremost technological advancement in this field. This review addresses three major topics in the field of LTx: first, we review the clinical manifestation of LIRI post-LTx; second, we discuss the pathophysiology of LIRI that leads to pulmonary endothelial inflammation and PGD; and third, we present the role of ESLP as a therapeutic vehicle to mitigate this physiologic insult, increase the rates of donor organ utilization, and improve patient outcomes.
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Ferdinand JR, Hosgood SA, Moore T, Ferro A, Ward CJ, Castro‐Dopico T, Nicholson ML, Clatworthy MR. Cytokine absorption during human kidney perfusion reduces delayed graft function-associated inflammatory gene signature. Am J Transplant 2021; 21:2188-2199. [PMID: 33098231 PMCID: PMC8246774 DOI: 10.1111/ajt.16371] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 10/16/2020] [Accepted: 10/19/2020] [Indexed: 01/25/2023]
Abstract
Transplantation is the optimal treatment for most patients with end-stage kidney disease but organ shortage is a major challenge. Normothermic machine perfusion (NMP) has been used to recondition marginal organs; however, mechanisms by which NMP might benefit organs are not well understood. Using pairs of human kidneys obtained from the same donor, we compared the effect of NMP with that of cold storage on the global kidney transcriptome. We found that cold storage led to a global reduction in gene expression, including inflammatory pathway genes and those required for energy generation processes, such as oxidative phosphorylation (OXPHOS). In contrast, during NMP, there was marked upregulation OXPHOS genes, but also of a number of immune and inflammatory pathway genes. Using biopsies from kidneys undergoing NMP that were subsequently transplanted, we found that higher inflammatory gene expression occurred in organs with prolonged delayed graft function (DGF). Therefore, we used a hemoadsorber (HA) to remove pro-inflammatory cytokines. This attenuated inflammatory gene expression increased OXPHOS pathway genes and had potentially clinically important effects in reducing the expression of a DGF-associated gene signature. Together, our data suggest that adsorption of pro-inflammatory mediators from the perfusate represents a potential intervention which may improve organ viability.
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Affiliation(s)
- John R. Ferdinand
- Molecular Immunity UnitUniversity of Cambridge Department of MedicineLaboratory of Molecular BiologyCambridgeUK
- National Institute of Health Research Blood and Transplant Research Unit in Organ DonationCambridgeUK
| | - Sarah A. Hosgood
- National Institute of Health Research Blood and Transplant Research Unit in Organ DonationCambridgeUK
- University of Cambridge Department of SurgeryCambridgeUK
| | - Tom Moore
- National Institute of Health Research Blood and Transplant Research Unit in Organ DonationCambridgeUK
- University of Cambridge Department of SurgeryCambridgeUK
| | - Ashley Ferro
- Molecular Immunity UnitUniversity of Cambridge Department of MedicineLaboratory of Molecular BiologyCambridgeUK
| | - Christopher J. Ward
- Molecular Immunity UnitUniversity of Cambridge Department of MedicineLaboratory of Molecular BiologyCambridgeUK
| | - Tomas Castro‐Dopico
- Molecular Immunity UnitUniversity of Cambridge Department of MedicineLaboratory of Molecular BiologyCambridgeUK
| | - Michael L. Nicholson
- National Institute of Health Research Blood and Transplant Research Unit in Organ DonationCambridgeUK
- University of Cambridge Department of SurgeryCambridgeUK
| | - Menna R. Clatworthy
- Molecular Immunity UnitUniversity of Cambridge Department of MedicineLaboratory of Molecular BiologyCambridgeUK
- National Institute of Health Research Blood and Transplant Research Unit in Organ DonationCambridgeUK
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Prasad NK, Pasrija C, Talaie T, Krupnick AS, Zhao Y, Lau CL. Ex Vivo Lung Perfusion: Current Achievements and Future Directions. Transplantation 2021; 105:979-985. [PMID: 33044428 PMCID: PMC8792510 DOI: 10.1097/tp.0000000000003483] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
There is a severe shortage in the availability of donor organs for lung transplantation. Novel strategies are needed to optimize usage of available organs to address the growing global needs. Ex vivo lung perfusion has emerged as a powerful tool for the assessment, rehabilitation, and optimization of donor lungs before transplantation. In this review, we discuss the history of ex vivo lung perfusion, current evidence on its use for standard and extended criteria donors, and consider the exciting future opportunities that this technology provides for lung transplantation.
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Affiliation(s)
- Nikhil K. Prasad
- Department of Surgery, University of Maryland School of Medicine
| | - Chetan Pasrija
- Department of Surgery, University of Maryland School of Medicine
| | - Tara Talaie
- Department of Surgery, University of Maryland School of Medicine
| | | | - Yunge Zhao
- Department of Surgery, University of Maryland School of Medicine
| | - Christine L. Lau
- Department of Surgery, University of Maryland School of Medicine
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Heinen N, Klöhn M, Steinmann E, Pfaender S. In Vitro Lung Models and Their Application to Study SARS-CoV-2 Pathogenesis and Disease. Viruses 2021; 13:792. [PMID: 33925255 PMCID: PMC8144959 DOI: 10.3390/v13050792] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/23/2021] [Accepted: 04/26/2021] [Indexed: 02/08/2023] Open
Abstract
SARS-CoV-2 has spread across the globe with an astonishing velocity and lethality that has put scientist and pharmaceutical companies worldwide on the spot to develop novel treatment options and reliable vaccination for billions of people. To combat its associated disease COVID-19 and potentially newly emerging coronaviruses, numerous pre-clinical cell culture techniques have progressively been used, which allow the study of SARS-CoV-2 pathogenesis, basic replication mechanisms, and drug efficiency in the most authentic context. Hence, this review was designed to summarize and discuss currently used in vitro and ex vivo cell culture systems and will illustrate how these systems will help us to face the challenges imposed by the current SARS-CoV-2 pandemic.
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Affiliation(s)
| | | | | | - Stephanie Pfaender
- Department of Molecular and Medical Virology, Ruhr-University Bochum, 44801 Bochum, Germany; (N.H.); (M.K.); (E.S.)
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Tatum R, O'Malley TJ, Bodzin AS, Tchantchaleishvili V. Machine perfusion of donor organs for transplantation. Artif Organs 2021; 45:682-695. [PMID: 33349946 DOI: 10.1111/aor.13894] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/25/2020] [Accepted: 12/17/2020] [Indexed: 12/16/2022]
Abstract
The ever-widening gap between organ supply and demand has resulted in an organ shortage crisis that affects patients all over the world. For decades, static cold storage (SCS) was the gold standard preservation strategy because of its simplicity and cost-effectiveness, but the rising unmet demand for donor organ transplants has prompted investigation into preservation strategies that can expand the available donor pool. Through ex vivo functional assessment of the organ prior to transplant, newer methods to preserve organs such as perfusion-based therapy can potentially expand the available organ pool. This review will explain the physiologic rationale for SCS before exploring the advantages and disadvantages associated with the two broad classes of preservation strategies that have emerged to address the crisis: hypothermic and normothermic machine perfusion. A detailed analysis of how each preservation strategy works will be provided before investigating the current status of clinical data for each preservation strategy for the kidney, liver, pancreas, heart, and lung. For some organs there is robust data to support the use of machine perfusion technologies over SCS, and in others the data are less clear. Nonetheless, machine perfusion technologies represent an exciting frontier in organ preservation research and will remain a crucial component of closing the gap between organ supply and recipient demand.
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Affiliation(s)
- Robert Tatum
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Thomas J O'Malley
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Adam S Bodzin
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, PA, USA
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Royston D, Alston RP. Cardiothoracic Anesthesia and Critical Care in the United Kingdom (UK) Part 1: Some Insights Into the History and Development. J Cardiothorac Vasc Anesth 2021; 35:3746-3759. [PMID: 33726943 DOI: 10.1053/j.jvca.2021.02.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/17/2021] [Accepted: 02/03/2021] [Indexed: 11/11/2022]
Abstract
This review is intended to highlight some of the historic events that contributed to the development of thoracic and cardiac anesthesia and surgery in Great Britain and Northern Ireland (UK). The aim of this first of two parts is to concentrate on the development of techniques, facilities, and pharmacology that allowed progress and advancement in patient management that were developed primarily in the UK. However, progress usually requires input from a wide variety of sources of knowledge, and cardiothoracic practice is no exception. Reference is, thus, made to sources outside of the UK that guided, influenced, or inspired changes in practice, such as the techniques of operating on the heart and great vessels in war casualties, developed by Dr. Dwight Harken, or the demonstration of the Blalock-Thomas-Taussig shunt by Alfred Blalock. In addition to advances in medical equipment, such as computed tomography, the UK contributed greatly to pharmacologic interventions that were unique at the time in such varied areas as nonflammable volatile anesthetic agents, heart failure treatments, and neuromuscular blocking agents for both cardiac and thoracic surgical practice.
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Affiliation(s)
- David Royston
- Department of Cardiothoracic Anaesthesia, Critical Care and Pain Management, Royal Brompton and Harefield NHS Foundation Trust, Harefield Hospital Harefield, Uxbridge, United Kingdom.
| | - R Peter Alston
- Department of Cardiothoracic Anaesthesia, Critical Care and Pain Management, Royal Infirmary of Edinburgh, Edinburgh, Scotland
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