Heart and Lung Transplantation: Science and Ethics of DCDD and Xenotransplants Hybrid Workshop

The National Institutes of Health’s (NIH) National Heart, Lung, and Blood Institute (NHLBI) hosted a two-day hybrid workshop on “Heart and Lung Transplantation: Science and Ethics of DCDD and Xenotransplants” on March 20-21, 2023. Experts in transplantation science and bioethics gathered to discuss the state of the science of organ donation after circulatory determination of death (DCDD) and related ethical issues, and the science and ethics of xenotransplantation. The objectives of the workshop were to discuss methods to address the shortage of hearts and lungs for transplantation by identifying knowledge gaps and opportunities for research. The first day consisted of a keynote lecture, followed by two sessions of presentations from groups of external experts who had been working together on specific, related topics for several months prior to the workshop. The focus was on DCDD science and ethics in the morning and on xenotransplantation science and ethics in the afternoon. On the second day, participants divided into six groups to address specific topics and questions raised during the first day and to identify research opportunities; they reconvened at the end of the morning to report on their work. More than four hundred participants attended the workshop virtually and in-person over the two days.

The findings, knowledge gaps, and opportunities described here represent a summary of individual opinions and ideas expressed during the workshop.  The summary does not represent a consensus opinion or directive made to or by NHLBI or NIH.

Background

Despite the increased growth of organ donation in the United States over the past several years, the heightened demand for hearts and lungs continues to greatly outpace the growth in supply. Addressing this problem begins with attempts to prevent and treat underlying medical conditions to avoid development of advanced heart and lung disease, such as, for example, addressing social determinants of health, managing hypertension and diabetes, and promoting healthy diets and smoking cessation. Management of end-stage lung disease or heart failure that develops in some patients can also be better optimized, thus avoiding disease progression to the need for transplantation and by advances in technology, such as left ventricular assist devices, that are now used as destination therapy rather than only as a “bridge to transplantation” with continually improving outcomes. Despite this progress, there are currently more than 3000 people in the U.S. awaiting heart transplantation, and more than 1000 awaiting lung transplantation.  New technologies and alternative sources of organs have also been explored as possible solutions to the gap between donor organ supply and demand. The NHLBI convened this workshop in March 2023 specifically to discuss the remaining gaps in knowledge of the science and ethics of two of these: organ donation following circulatory determination of death (DCDD) and xenotransplantation. 

Discussions

In her keynote address, Ms. Glazier introduced a concept she called impatient optimism as a practical and legal perspective to meet the demand for donor organs for transplantation through deliberate and optimistic actions that consider transparency, public trust, and urgency. The number of organ donors registered in the United States has continued to increase over time; however, the demand for organ transplants has outpaced this growth in supply. One of the principal areas of growth seen over the last five years is due to a 124% increase in the number of DCDD donors. Newer technologies and innovations have been developed and implemented in DCDD to optimize organ utilization. However, the use of these technologies raises ethical and legal issues that must be considered within frameworks that currently rely on non-uniform definitions of death as well as other non-standardized terms relevant to transplantation science.

Session 1: DCDD Donors
Four groups of scientists, clinicians, and ethicists had worked together prior to the workshop to identify the most pressing ethical and conceptual questions related to DCDD. The underlying tension complicating the use of DCDD is between the need to be certain that the donor has died prior to organ procurement, and the need to optimize organ preservation. Two working group leads discussed the current science of DCDD, followed by two presentations on relevant ethical considerations. A major point of discussion was the need to develop a universal understanding of when a person is dead in the context of the DCDD organ donor. Defining death has medical, legal, ethical, and practical implications that must be considered and evaluated before a consensus decision can be made. This task is further complicated by the introduction of technologies such as normothermic regional perfusion (NRP), which circulates oxygenated blood in specific regions of the body after death. The principal point of controversy is whether the reintroduction of circulation by NRP contradicts the prior donor death determination, which was predicated on the ”irreversible” cessation of donor circulation. Standardized terminology, training, and protocols for the withdrawal of life support (WLS) were also suggested to increase utilization of organs by improving organ assessment techniques and minimizing damage to organs prior to procurement, but an evidence base to support such guidelines is lacking. These actions must balance optimal donor management with optimal end-of-life care, and must also account for variations between the different organs to be donated and the unique challenges associated with each. The presentations were followed by a panel discussion which allowed participants to further consider the more complex challenges regarding the science and ethics surrounding DCDD.

Session Two: Xenotransplantation
Xenotransplantation was discussed as a potential alternative strategy to supplement the supply of organs needed for transplantation. Using porcine organs in non-human primate (NHP) and other pre-clinical models has enabled research into the potential of human xenotransplantation and some of its associated risks. The current work regarding combinations of genetic modifications to porcine tissues and novel immunosuppressive regimens was discussed, and the need for further studies, including clinical trials, was emphasized. The potential for zoonotic infections was highlighted as an important consideration, as infectious diseases may impact the staff that performs the xenotransplantation, the recipient of the xenograft, and other contacts of the recipient. Various concerns surrounding the ethics of xenotransplantation were discussed including informed consent and what the appropriate selection criteria for xenograft recipients might be. 

Additionally, the use of deceased donor models was discussed as a model to bridge the gap between NHP pre-clinical models and Phase 1 clinical trials in living human recipients. Deceased donor models utilize whole-body donations from those who wished to donate organs but did not meet the eligibility criteria to do so. These models involve a ventilated, heart-beating human who is declared dead based on neurological criteria, to allow researchers to optimize pre-clinical protocols by using xenografts in non-living human subjects while mitigating safety concerns. The unique challenges involving the use of deceased donor models were discussed, including how to approach families, how to determine the appropriate and acceptable time and procedural limits for use of the decedent, in which type of facility this work should be conducted, what kind of oversight might be needed, and whether healthcare staff should be able to opt out of such work. 

Day Two: Breakout Discussions 
During the second day of the workshop, following a brief recap of Day One and review of the pre-workshop survey results, participants broke into groups with the purpose of identifying research gaps and opportunities within the field of transplantation science and ethics. The intention was to “remix” the scientists and ethicists who had met prior to the workshop and add other workshop attendees to the discussion. Each group was tasked with discussing a particular topic from the previous day’s sessions. Those topics included informed consent and permission; patient selection for xenotransplantation, preclinical model development for xenotransplantation and DCDD, the information required to inform regulatory issues, how to agree on a standard definition of death, and identification of priorities for the development of DCDD technologies. There was much overlap in discussion between the given topics and several of the key research opportunities identified are listed below. 

Basic and Clinical Science Research in DCDD

• Research in end-of-life care: what is the best way to withdraw life support in order to both optimize the donor’s and family’s experience (comfort and dignity) as well as their desire to donate organs (organ preservation).
• Research in resuscitation science to determine the appropriate “hands off” or waiting period for pediatric and adult donors between the cessation of vital signs and death determination that affords both certainty of the death of the donor as well as optimizing preservation of organ function, recognizing that this time period may be different (and likely longer) in children and particularly in neonates. 
• Ongoing research in organ preservation, specifically as it relates to DCDD. 
• Investigate how variations in organ preservation and assessment techniques and procedures affect utilization and clinical outcomes, with a goal to inform standardization of practices in order to mitigate organ injury and optimize utilization.

Basic and Clinical Science Research in Xenotransplantation 

• Further investigate predictive modeling to identify potential zoonoses and develop assays validated in various tissues to detect such infections and to prevent disease transmission.
• Study factors that will inform criteria for the selection of xenograft recipients, including those related to outcomes but also ethics and equitability considerations. 
• Further investigate the appropriate genetic modifications to porcine tissues and the most effective immunosuppressive regimens.

Implementation Science Research Related to Organ Donation and Transplantation

• Determine when, how, and by whom families should be approached about withdrawal of life support and the possibility of organ donation. 

Investigate barriers to organ donation as well as ways to increase receptiveness to donation among specific demographic groups, including racial and ethnic minorities and pediatric donation.

Empirical Bioethics Research in DCDD and Xenotransplantation

• Investigate the public conception of death, particularly as related to DCDD with and without NRP, and of the determination of death as related to irreversible or permanent (irreversible by intention) loss of circulatory and/or brain function.
• Investigate how much the public understands about DCDD procedures, the techniques used during procurement, and their views on the morality of DCDD.
• Investigate how public perception can impact donor pools and the willingness of individuals and families to donate under DCDD protocols. Do Americans approve or support the expansion of the use of DCDD?
• Determine what information about DCDD is scientifically and ethically relevant to share with potential donors and surrogate decision makers to better assist them in making informed decisions about organ donation. 
• Determine how much information is required to provide truly informed consent for xenotransplantation. Given the current state of the science, is informed consent even possible?
• Determine how much information is necessary to provide truly informed consent by families and/or surrogates in deceased donor models.
• Determine the ethically appropriate length of time for use of the deceased donor model and the contingencies that should exist for timely return of the body to the family.

Workshop Participants

Co-Chairs:
James Bernat, M.D., Dartmouth College
Kiran K. Khush, M.D., M.S., Stanford University

NIH Co-Leads:
David Goff, M.D., Ph.D., FACP, FAHA, National Heart, Lung, and Blood Institute
Kathleen Fenton, M.D., M.S., National Heart, Lung, and Blood Institute

Speakers and Moderators:
Judith Arcidiacono, M.S., U.S. Food and Drug Administration
Anne Dalle Ave, M.D., M.S., Georgetown University
Alexandra Glazier, J.D., MPH, New England Donor Services
Matthew Hartwig, M.D., MHS, Duke University
David Klassen, M.D., University of Utah
Muhammad Mohiuddin, MBBS, University of Maryland
Robert Montgomery, M.D., D.Phil, FACS, New York University
Brendan Parent, J.D., New York University
Richard Pierson III, M.D., Harvard University
Peter Reese, M.D., Ph.D., University of Pennsylvania
Ciara Martin Shaver, M.D., Ph.D., Vanderbilt University
Sam Shemie, M.D., McGill University
Henry Silverman, M.D.M.A., University of Maryland
Daniel P. Sulmasy, M.D., Ph.D., Georgetown University
Robert D. Truog, M.D., M.A., Harvard University

Working Group Members:
Andrew Adams, M.D., Ph.D., University of Minnesota
Isaac Alderete, M.D., M.S., Duke University
Alexander Capron, M.D., M.S., University of Southern California
Marcelo Cypel, M.D., M.Sc., FRCSC, University of Toronto
Jay A. Fishman, M.D., Harvard University
Teneille Gofton, M.D., FRCPC, Western University
Elisa J. Gordon, Ph.D., MPH, Vanderbilt University
Michael Gusmano, Ph.D., Lehigh University
Wayne John Hawthorne, M.D., Ph.D., MHSc, University of Sydney
Andrew Healey, M.D., McMaster University, William Osler Health System
Mary E. Homan, Dr.PH., M.A., MSHCE, CommonSpirit Health
Clint Hostetler, RN, BSN, MHA, LifeShare Transplant Donor Services of Oklahoma
Daniel J. Hurst, Ph.D., Th.M., M.Div., M.Sc., Rowan University
Keren Ladin, Ph.D., M.Sc., Tufts University
Stephen Latham, J.D., Ph.D., AB, Yale University
Riley Lopez, MBA, Vascular Perfusion Solutions, Inc.
Karen J. Maschke, Ph.D., The Hastings Center
Kenneth McCurry, M.D., Cleveland Clinic
Franklin Miller, Ph.D., National Institutes of Health
Nick Murphy, Ph.D., Western University
Thomas A. Nakagawa, M.D., FAAP, FCCM, University of Florida
Chung-Gyu Park, M.D., Ph.D., Seoul National University
William F. Parker, M.D., Ph.D., University of Chicago
Rebecca Pentz, Ph.D., Emory University
Prof. Dr. Dr. h.c. Bruno Reichart, M.D., Ph.D.
David Rodriguez-Arias, Ph.D., University of Granada
Pablo Sanchez, M.D., Ph.D., FACS, University of Pittsburgh
Julian Savulescu, Ph.D., Oxford University
Scott Silvestry, M.D., AdventHealth Transplant Institute
Joseph W. Turek, M.D., Ph.D., MBA, Duke University
Marian Urban, M.D., Ph.D., University of Nebraska
Anji Wall, M.D., Ph.D., FACS, University of Texas
Stephen P. Wall, M.D., MSHS, MAEd, New York University
Paul Root Wolpe, Ph.D., Emory University

NIH Staff:
Catherine Burke, M.A., National Heart, Lung, and Blood Institute, NIH
Matt Craig, Ph.D., National Heart, Lung, and Blood Institute, NIH
Jonah Ndukwo Kalu Odim, MBA, M.D., Ph.D., National Institute of Allergy and Infectious Diseases, NIH
Nina Roesner, J.D., Department of Bioethics, NIH Clinical Center
Bryanna N. Schwartz, M.D., M.P.H., National Heart, Lung, and Blood Institute, NIH
Wendy Taddei-Peters, Ph.D., National Heart, Lung, and Blood Institute, NIH
Renee Wong, Ph.D., National Heart, Lung, and Blood Institute, NIH

Agenda

Heart & Lung Transplantation: Science & Ethics of DCDD and Xenotransplants Hybrid Workshop
March 20-21, 2023

Agenda

Monday, March 20th – 8am - 5pm

Tuesday, March 21st - 8am - 12:00 noon