Introduction

As the demand for a life saving organ donation increases, with over 100,000 individuals in the US alone on the waiting list, the supply of organ donations falls short, with under 50,000 transplants performed in 2023.¹ On average, 16 individuals die each day while waiting for a life saving organ that never comes.² With just these numbers in mind, it is no surprise that the face of modern medicine is actively searching for methods of increasing the amount of life saving organs that become available to the individuals on the waiting list. Donation occurs via two methods, donation after cardiac death or donation after brain death. Donation after brain death is more common since the patient is pronounced dead while the heart is still pumping oxygenated blood to the organs that are being prepared for donation.³ Donation after cardiac death produces less viable organs for transplantation on average due to the warm ischemia time, or the time that an organ is at body temperature after it is no longer being perfused with oxygenated blood.^3,4 Normothermic Regional Perfusion (NRP) has recently been applied as a method of keeping these potential donor organs perfused with oxygenated blood after the donor's heart stops in a donation after cardiac death procedure, effectively increasing the pool of donors from whom organs can be successfully transplanted.

This procedure has come with some controversy, ”Because the procedure involves restarting blood flow after the heart and circulation have stopped, some ethicists and surgeons say it invalidates any previous declaration of death.”⁵ Further, during this process clamps are used to cut off blood flow from getting to the brain to limit any chance that any brain activity could be restored when blood circulation begins once again. These two facts have split the medical community and ethics committees around the country. Notably, NYU Langone Health in Manhattan was the first hospital to take on this procedure in the US back in 2020. Yet within the same city, NewYork-Presbyterian Hospital, the home of the city’s largest organ transplant program, has denied the use of this technique after an ethics review.⁶ The aspect of this procedure that troubles ethicists is the restarting of blood circulation after the initial pronouncement of death. Some believe that this restarting of circulation invalidates the initial pronouncement of death. Further, in order to ensure that a significant amount of blood flow does not get to the brain and restore any activity, metal clamps are attached to arteries.

Throughout this paper, NRP will be analyzed as a method of increasing the pool of potential donor hearts and alleviating the organ shortage crisis. There is no doubt that this method is capable of expanding the amount of donor hearts available for individuals in need, the question is if this method is justifiable and morally sound. The procedure and its implications will be analyzed historically, medically, legally, and ethically. Ultimately, this paper aims to provide a comprehensive review of the technique and to make recommendations regarding its proper use.

History

A historical overview of NRP requires a brief mention of the origins of organ donation in general followed by a more specific description of the emergence of this method and conversations about it in the US.

The first successful human organ transplantation in the US was a living donor kidney transplantation that occurred in Boston in 1954 between identical twin brothers.⁷  However, the first successful transplantation from a dead donor was a kidney that was donated in 1962.⁸ From then until 1968, the predominant form of organ donation was after cardiac death of the donor (DCD) due to vague and unestablished neurologic death criteria. It was in 1968 that a committee at Harvard Medical School published the “Harvard Criteria for the Determination of Death” in which the diagnostic criteria for irreversible loss of brain function are described.⁹ This publication preceded by 13 years the release of the Uniform Determination of Death Act of 1980 that stated that death is the result of either irreversible breathing and circulatory function or irreversible cessation of all brain functions, including the brainstem.⁸ This formed a model law for states to mimic.⁸ Since then, donation after brain death (DBD) has become the predominant form of organ donation due to the ability to maintain perfusion of organs and avoid ischemic damage as compared to DCD. And while it was estimated that DCD accounted for about 20% of transplanted organs in 2018, the reason it is not more is because of the aforementioned ischemia that results from a temporary loss of perfusion to organs required for pronouncement of cardiac death.¹⁰

Utilization of organs from DCD patients specifically have increased substantially over the last 30 years.¹¹ According to the Scientific Registry of Transplant Recipients, the number of organs recovered from DCD patients rose from 112 in 1993 to over 10,000 organs in 2021.¹¹ This increase is consistent with the proportion of organs retrieved from DCD patients. In 1994, only 0.7% of all recovered organs were from DCD patients, whereas in 2021, this number was up to over 20%.¹¹ This shift has been attributed to a number of factors, including but not limited to the technological advances that allow for improved ability to prolong organ perfusion with machines and the resolution of certain ethical dilemmas surrounding the withdrawal of life-supporting treatment.¹¹

            However, issues persist, particularly concerning certain methods through which organs obtained from DCD patients are preserved and maintained. While the specifics of these procedures will be described in detail below, in general, techniques exist, like extracorporeal organ support (ECOS), that can maintain perfusion of an explanted heart ex vivo or more recently, help reestablish circulation in situ.¹² This latter technique is called Normothermic Regional Perfusion (NRP) and requires the blocking of arteries to the brain to prevent re-circulation to the brain. This technique was first used in 1989 in Spain and since has been used widely in Europe due to high success rates for organs like the kidney and liver.¹³ NRP is used in the US as well, more commonly for livers than for hearts, but discourse to this point has focused predominantly on this procedure for heart transplantation due to the organ’s particular vulnerability to ischemic damage in DCD patients.

Surgeons at Cambridge in England began trying this procedure for heart transplantation starting in 2015, and while some US hospitals have utilized England as a paradigm, others are hesitant to do the same, citing ethical concerns.⁶

The current ambiguity surrounding NRP among US hospital systems can be aptly represented by the situation between two hospitals in New York City and the current discrepancy in stances on this issue between medical societies themselves. NYU Langone in Manhattan first performed the procedure in January 2023 in a 43-year-old donor with end-stage liver disease, leading to a successful retrieval and subsequent transplantation of a functional heart.⁶ NYU Langone has since continued the utilization of this procedure, resulting in dozens more successful heart transplantations.⁶ However, nearby NewYork-Presbyterian Hospital has prohibited the use of the technique after analysis from their ethics committee.⁶ The American College of Physicians (ACP) has publicly opposed the practice, stating that proponents of NRP have not yet met the burden of proof required to show that this procedure is not in conflict with the definition of death in the US.¹⁴ However, the American Society of Transplant Surgeons has recently reached a consensus in support of the procedure, stating that the procedure itself is not in violation of any essential bioethical concepts and should be offered so long as donor and donor family autonomy are prioritized.¹⁵

Thus, the potential of this procedure to increase the number of viable organs for donation has become evident, but experts remain at odds over legitimate ethical concerns. 

Medical Perspectives

Dead Donor Rule

The world of organ donation is grounded in an underlying principle known as the “Dead Donor Rule” (DDR), which states that a donor must be first declared dead by legal and medical standards before the organs are procured. This stems from the widely accepted belief that one should not kill a person to save another. The Uniform Determination of Death Act (UDDA) was then created in 1981 to define death. The language of the act is as follows:

An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead. A determination of death must be made in accordance with accepted medical standards.

DDR allows physicians to be confident in the process of organ transplantation, as this ethical code aligns with the oath of “first do no harm” since the organs would only be transplanted after declaration of death using the above stated law.

Upon closer examination, the second point of UDDA, namely brain death, aligns with DDR because the patient is considered dead by widely accepted medical standards allowing transplant teams to harvest the organs in the best condition possible since the rest of the body is functionally intact, including the heart. However, donation after circulatory death (DCD) as stated in the first point of UDDA, poses a challenge.¹⁶ Circulatory death is when all life support has ceased for at least 60 minutes and there is no spontaneous circulation.¹⁶ Current protocol requires waiting 2-5 minutes after this to begin organ procurement making a total of roughly 70 or more minutes of ischemia if you factor in surgical procedure as well.¹⁶ This rule significantly diminishes or even eliminates the viability of the heart, greatly reducing available hearts to transplant.¹⁶

In this section, we intend to reconsider the DDR and examine the medical aspects of Normothermic Regional Perfusion (NRP), its implication on heart transplants from DCD donors, and the ethical questions that ensue.

To begin with, DDR itself needs a re-examination. It has the potential to prevent organ donation, such as when terminally ill patients want to donate their organs according to their own will but the Dead Donor Rule necessitates the patient to be dead, which would require cessation of circulation for roughly 70 mins, rendering organs unusable. DDR existed and evolved as a liability prevention tool protecting physicians of wrongful accusations such as “killing someone for organs.”¹⁷ Hence, as Scott J. Schweikart mentions in his article, we should consider alternative practices, which allow “imminent death donation” wherein a critically ill patient with impending death can choose to donate or have a will that states it, enabling procurement of organs when circulation is intact.¹⁷ Another interesting methodology is “live donation prior to planned withdrawal” in a brain-dead patient. Living Will and Advance Directives would have to undergo changes to incorporate this change, but these types of changes would encourage organ donation while protecting physicians. Recent studies reveal public support on the same matter.¹⁷

Donation after Circulatory Death (DCD) and NRP

Hearts have traditionally been obtained from brain dead donors, as those are usually the only candidates in whom cardiac viability is maintained through determination of death. However, during the last decade, explanting hearts from those declared dead by DCD rule has gained traction.¹⁸ In 2016, expanding DCD donation led to a 20% contribution to a total of 34,854 deceased donors as reported to the Global Observatory on Organ Donation and Transplantation.¹⁸ In the majority of the cases, organs were obtained by a controlled DCD (cDCD), which includes death by planned withdrawal of care.¹⁸ This process boosted the availability of most organs such as pancreas, kidney, liver, and lung, but heart availability continued to lag behind. This is a consequence of the 60-minute waiting period as stated by UDDA, which greatly reduces viability of the heart.

It should be noted that some studies have succeeded in demonstrating that patients with hearts obtained from DCD patients had similar overall survival as compared to brain dead donor hearts.^19,20,21

Hence, we need a tool which preserves cardiac perfusion in a DCD patient, potentially increasing the number of viable hearts available for donation. One such tool is Normothermic Regional Perfusion (NRP).

NRP is a method of maintaining organ perfusion in cDCD patients.¹⁰ Here, Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO) is used to maintain perfusion to abdominal and thoracic organs after withdrawal of life support.¹⁰ Currently, thoraco-abdominal (TA-NRP) and abdominal NRP (A-NRP) are in practice.

In TA-NRP, life support is first withdrawn. If the donor dies anytime within 30 minutes of withdrawal, a mandatory ‘hands-off’ period is enforced to avoid auto-resuscitation. After circulatory support withdrawal and cessation of electromechanical activity of the heart, the thorax is entered quickly, followed by opening the pericardium and cannulation of the aorta (arterial cannulation) and right atrium (venous cannulation). Immediately after this, the innominate and carotid arteries are clamped to prevent blood flow to the brain. This establishes the VA-ECMO flow. Usually, the heart regains activity in 2 to 3 minutes after initiation of perfusion.²² Flow of NRP is then titrated to obtain a cardiac index of 2 or greater, and the intra-aortic pressures are monitored. In the University of Wisconsin method, surgeons maintain perfusion for 45 minutes followed by slow weaning to allow at least 2 minutes of independent cardiac activity. The cardiac surgeon then evaluates the heart visually while it works under physiologic loading conditions. Once deemed viable and suitable, NRP is re-established and the implanting surgeon is informed in order to begin surgery to receive the organ. Meanwhile in some settings, blood levels of lactate and potassium are measured to assess for ischemia. Once cardiac contractility is determined to be adequate, venous cannulation is removed while leaving the aortic cannula (arterial cannulation) in place as this allows continuous perfusion of the abdominal organs. Once the abdominal and thoracic teams are ready, that aorta is cross-clamped, and all the necessary organs are removed.^10,22

Advantages of NRP for cardiac availability

In comparing the standard DCD procedure to the NRP DCD, both procedures begin after the donor has been declared dead and a specified time frame has passed where there has been no autoresuscitation. A sternotomy and laparotomy are performed for organ access and subsequent procurement.²³ 

In the standard DCD procedure, the aorta is cannulated, and cold perfusion is done for the purpose of organ preservation, and blood is exsanguinated from the body. The heart is then restarted using a machine that lies outside of the body.²³ With NRP DCD, the brachiocephalic arteries are occluded to prevent reperfusion to the brain, right atrium and aorta are cannulated and normothermic perfusion is started using ECMO which then circulates blood to the organs. The difference with this procedure is that the heart is restarted within the body and is done only for the purpose of organ donation.²³ 

There are several medical advantages of NRP over the alternative method of removal of the organs before reperfusion extracorporeally. First, continuous warm blood perfusion restores heart function, reduces myocardial injury, promotes energy storage, and maintains homeostasis.10 Second, NRP reduces the time spent by the heart in warm ischemia.¹⁰ Lastly, keeping the heart and abdominal organs in situ during reperfusion allows for assessment of the organs prior to retrieval.10 This permits evaluation of organ viability as well as a visual assessment of the organs while still in the body.¹⁰

The cerebral perfusion conundrum

Neuronal hypoxemia and ischemia occur in both the standard DCD donation and NRP DCD donation. Neuronal hypoxemia and ischemia progress, as cold reperfusion does not reperfuse the brain inherently and the clamping of the brachiocephalic vessels in NRP prevents oxygenated blood from reaching the brain.²³ To ensure a lack of reperfusion to the brain despite clamping of the brachiocephalic vessels, one research study suggested diversion of collateral arterial brain blood flow to drain to the atmosphere.²⁴ The main question to answer is what additional protocols or assurances can be made to ensure that the return of brain perfusion is avoided. There are several collateral circulations that could in theory restore flow to the brain. Collaterals arise from the thoracic aorta connecting to the posterior intercostals which ultimately connect to the anterior spinal artery, the inferior epigastric artery, which connect to the internal thoracic artery and then the subclavian and vertebral arteries, the thoracic aorta to supreme intercostal artery, which then connects to the subclavian and vertebral arteries, and thyrocervical trunk to ascending cervical artery to the vertebrobasilar system.²⁴ The proposal, according to Manara, suggests that a large bore cannula be placed cephalad to the abdominal aortic clamp into the ascending aorta or aortic arch vessels.²⁴ This drain is open to the atmosphere or to negative pressure and would help to prevent collateral blood flow from reaching the brain.²⁴ The blood is drained into a venous reservoir for transfusion and perfusion back to the abdominal and thoracic organs.²⁴ In practice, Manara’s findings suggest that properly occluded descending aorta is enough to prevent collateral circulation and thus brain perfusion in A-NRP, as there was a lack of flow out of the ascending aortic cannula combined with minimal pressure readings ranging between 0-3 mmHg.²⁴ With TA-NRP, there is no sure-fire way to avoid reperfusion to the brain tissues. However, the rate of blood flow from the aortic arch vessels left open to drainage is not enough for adequate neuronal function. Therefore, the process of neuronal death and ischemia is left uninterrupted.²⁴ 

With the standard DCD procedure, following withdrawal of life support, the autonomic response which is led by a drop in cerebral perfusion increases the levels of catecholamines inducing an alpha receptor mediated vasoconstriction to organs like the lungs and liver leading to significant ischemia. This period of ischemia is directly associated with the higher incidence of biliary complications in DCD livers for example.²⁵  The primary reluctance in using organs from donors after circulatory death is the wide array of effects of cessation of circulation, as organs depend on ideal oxygen levels and electrolyte concentrations for optimal function. Additionally, warm ischemia becomes a concern once reperfusion is undertaken.

Recent studies have demonstrated good short-term outcomes with extended ischemic times using NRP.²⁶ 

One study out of the UK revealed that the use of NRP allowed for great organ recovery, transplantation rate, and good graft survival rates compared to standard DBD and DCD practices in heart, liver, and kidney transplants.²⁵ The delayed graft function rate in kidney transplants was lower than the rest of the UK and 12-month clinical outcomes were encouraging in terms of graft survival.²⁵ 

Regarding the potential of organs being damaged in the time preceding and during transplantation, the data appears to be reassuring given the advancements in organ transplantation. Damage to kidneys via DCD procurement has decreased since 1999 with only 1% of kidneys not transplanted due to overt damage. The use of NRP may help to continue to reduce damage to organs upon procurement, effectively increasing the chances of graft survival.²⁷ 

A retrospective chart review comparing cases of cohorts who were transplanted DCD livers without NRP and those who were transplanted DCD livers with NRP, reveals that the NRP is a major factor in the reduction of post-transplant complications such as ischemic cholangiopathy. Ischemic cholangiopathy has been a known complication of livers procured via standard DCD protocol. Current standard practices attempt to limit vessel necrosis and microthrombi formation through regular flushing of tissues with thrombolytic agents such as TPa and urokinase. NRP for liver transplantation seems to reduce arterial and biliary necrosis without the need for thrombolytic agents.²⁸ Another limiting factor of organ procurement is donor age. With standard DCD protocols, biliary complications and ischemic cholangiopathy are seen in donors aged 50 and older. There is data that suggests good clinical outcomes in NRP use for liver transplant in donors ages 65 and older.²⁸ 

Additionally, NRP for liver transplantation allows for real-time monitoring of liver function with the possibility of obtaining serial transaminases and lactate levels which is done in standard medical practice to assess acute and chronic liver injury.²⁸ Lactate levels are inversely associated with degree of perfusion. Cessation of blood flow and oxygenation then causes a rise in lactate levels. Studies have shown that the use of NRP, especially in liver transplantation, reduces lactate levels and thus reflects optimal organ perfusion leading to successful organ procurement and transplantation.²⁸ 

With NRP, the active functional assessment of organs can be done in lieu of transplantation, which helps predict function within the recipient. Without the functional assessment, surgeons would be dependent on perfusion lactate levels to arrive at a determination of transplantation or lack thereof. NRP allows for real time monitoring of functional assessment without the need for serial biomarkers to be trended and followed. In Messer 2016, coronary perfusion reduced warm ischemia time significantly by helping to restore coronary perfusion by 10 to 20 minutes. DCD hearts had coronary perfusion restored by 23 to 28 minutes.²⁹ Messer 2016 highlighted that the use of NRP allowed for an increase in cardiac transplant activity by almost 50%.²⁹ 

Although promise has been shown in DCD organ donation in adults, the same cannot be said for pediatric DCD donations. The literature available is limited to small case series and animal studies seen with lung transplant while DCD heart transplantation remains primarily experimental.³⁰ Donor registries and mechanisms to allow donor recruitment such as the Department of Motor Vehicles are available for the adult population whereas no such mechanism exists in the pediatric population.³¹ 

Legal Aspects

In examining the legal aspects of this issue, an understanding of the legal definition of death must be established as well as an analysis of the crucial intersection between death and the NRP procedure.

The current definition of death followed by most states is the one from the aforementioned 1980 UDDA.³² This act establishes that under US law, an individual is dead when circulation has ceased and will not return following either auto-resuscitation or medical intervention of any kind.³³ And, while the NRP procedure, like all donation after cardiac death (DCD) procedures, declares death following these criteria, following this declaration, NRP protocols require the return of circulation to the body using artificial intervention.³³ Thus, NRP intersects with the definition of death at this crucial junction. Additionally, when considering the ethical norm of the Dead Donor Rule, which states in general that organ donors must be dead before organ procurement begins or that organ procurement cannot be the cause of death of the donor, this conflict with the definition of death is illuminated.³⁴

            Some proponents of NRP argue that when circulation is re-introduced during the NRP protocol, there is never an intent to resuscitate the patient, as this would be medically ineffective.³³ Others similarly use the idea of intent to argue that acts to preserve organ viability are in line with the intentions of the patient or surrogate who intended to donate the organs.³³ In response to this, it should be noted that the current legal definition of death does not take into consideration intention of any kind.³³ It solely relies on the physical condition of the patient.³³ A corollary to these facts is an argument that occlusion of a patient’s carotid arteries during NRP protocol is an effort to ensure a patient’s death by preventing temporary restoration of brain function that may result from recirculation.³³

 Given these concerns, there are possible alternative approaches that can rid NRP of legal conflict. These approaches are listed here, but our formal stance and recommendations are presented in a later section.

First, proponents may focus on the criteria for “circulation” and use perfusate instead of oxygenated blood to restore physiological support to the organs after death is declared.³³ By avoiding the use of oxygenated blood to restore function to the organs, proponents may argue that “circulation” is not being restored and maintain the “irreversible” nature of the cessation of circulation in the patient. Opponents may rebut and claim that some clinical procedures involving perfusate, such as ex vivo support for organs, utilize a mixture composed of red blood cells for the delivery of oxygen and nutrients to the body, and thus, the use of cells can still be considered restoration of circulation.³⁵ However, synthetic and acellular perfusates are in development now and could be an option for proponents of NRP in this argument.

Another option for proponents could be declaration of death based on loss of neurological function following removal of the ventilator and asystole.³³ In this scenario, given the language of the UDDA, contradicting the standard of “irreversible cessation of circulation” would no longer be relevant legally, as the patient was declared dead through the other criterion.³³ However, the time needed to make this diagnosis may compromise the viability of the organs of interest.³³

Third, there is consideration among the Uniform Law Commissioners concerning revising the definition of death, which provides the opportunity to address the conflict between the current definition and the challenges presented by advancing technologies in medicine, such NRP.³³ However, a redefinition of death with an eye towards increasing organ donation rates could foster public mistrust in death determinations, and the possible side effects this could have on public willingness to donate organs must weigh heavily in any such decisions.³³

Lastly, and perhaps most optimistically, leaders in transplant research could develop new more effective methods to preserve organ viability ex vivo that would circumvent any dangers associated with reperfusing organs within the body of a patient.³³

Ethical Analysis

The issue of NRP has raised serious interdisciplinary concerns. Many ethicists have called for a public debate on the issue of NRP that would examine all aspects of it including the ethical and moral implications. These issues include whether NRP is consistent with the DDR, are the protocols consistent and transparent, and does it respect the donor’s informed consent. The advantages of using NRP, as stipulated above, include increasing utilization and longevity of organs, saving more lives, decreasing post-transplant morbidity and providing comfort to donor families.  Opponents argue that donors and donor families do not always fully comprehend NRP and have concerns about the process. This can cause additional psychosocial distress.  It is also argued that NRP can increase a loss in public trust. This harm can be amplified given the current mindset of Americans regarding scientific and public health misinformation. This could lead to a decrease in the number of people willing to consent to deceased or living  organ donation. If this is going to be an open debate with all parties participating, then all options must be placed on the table, including the option that we should not proceed with NRP. To determine if this procedure is ethical, the principles of respect for persons, beneficence and nonmaleficence will be applied to this procedure and its consequences.

Respect for persons

This principle incorporates two ethical convictions: first, that persons should be treated as autonomous agents; and second, that persons with diminished autonomy are entitled to protection. The principle of respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.³⁶ Respect for human persons refers to the right of a person to exercise self-determination and to be treated with dignity and respect. All people deserve autonomy and to be treated with dignity and respect. Failure to provide any person with adequate health care, which includes clinical research and trials, violates this basic right of respect for persons. Appropriate funding for clinical research will increase our understanding of NRP, which will inform future research, and hopefully should result in the development of new, more effective standardized protocols that will increase the public’s understanding of NRP. “Respect for persons requires honoring the potential donors and their family’s preference for receiving information about NRP, as well as the intentions and wishes to become a donor, and to make the best possible use of this donation. Moreover, respect for persons acknowledges the importance of donor families in acting as surrogate or authorized decision-makers, acting in accordance with the preferences, values, and expectations of donor candidate patients.”³⁷ Additional research data on NRP would allow the duty to honor the potential donor or donor's proxy consent to organ donation and potentially save many more lives.

Second, as an autonomous agent an individual has the right of informed consent. Donors and Donor Proxies have the right to know all information about the donation process, the donation procedures, the risks, benefits and alternatives. The  elements of informed consent include:

1)A fair explanation of the procedures to be followed, including an identification of those which are experimental;

2)A description of the attendant discomforts and risks;

3)A description of the benefits to be expected;

4)A disclosure of appropriate alternative procedures that would be advantageous for the subjects;

5)A offer to answer any inquiries concerning the procedures;

6)An instruction that the subject is free to discontinue participation in the project or activity at any time.³⁸

In a specific sense, the surgeons who want to perform the NRP have an ethical obligation to give an objective, unbiased assessment of all materially relevant information pertaining to the success of NRP, risks/benefits, alternatives and consequences. The surgeons are also responsible to verify, to the best of their ability, that the donor or donor’s proxy can comprehend and has comprehended the information and has not engaged in “selective hearing.” Under the circumstances, it is not uncommon for donors or donor proxies to engage in “selective hearing,” that is, taking in all information about potential benefits and filtering out all information about potential risks. In addition to this, surgeons must be vigilant against their influence over donors and donor proxies, who may unwarily treat the surgeon with the same deference as they treat their primary care physicians. Dr. Robert Levine, professor of Medicine at Yale University, describes the surgeon/researcher’s obligation as one of “forthright disclosure.” This includes preliminary evidence and data from animal studies and previous human clinical trials that indicate the risks and benefits as well as the safety and efficacy of these controlled studies.³⁹ Patients need to have information that a prudent person would require to make well-reasoned decisions that will protect their personal interest.

The problem is determining what sort of knowledge translates to what degree of risk to patients. This is a value judgment that must be made by the surgeons. The concern is that the judgment of some surgeons may be biased by considerations of career self-interest and even financial gains.⁴⁰ “The potential for coercion can be difficult for surgeons. On the one hand, most accept that the final choice for surgery should be left to the donor or donor proxies. On the other hand, surgeons want what they believe to be best for the donor. Therefore, there is ample room for unintentional coercion through selecting information for disclosure that overtly reinforces the surgeon’s beliefs.”⁴¹ There is also the problem of forming an “innovative alliance.” Donors or a donor’s proxy may encourage the transplant surgeons to try any new and promising technique to improve organ donation and surgeons also may be eager to apply a promising new technique for the same reasons. It is the duty of the surgeons to decide whether responsible behavior lies in attempting an innovative technique like NRP or in concluding that the background research is not sufficient to warrant its use, even when the donor consents.⁴² The surgeon has the responsibility to act in the best interest of the donor. The belief that this experimental surgical procedure will not cause too much harm to too many people or that society will benefit at the possible expense of particular individuals violates the duty of the transplant surgeon to act in the best interest of the donor. To determine whether that duty has been breached, a transplant surgeon’s actions should be measured against the accepted practice as set by professional norms. Those surgeons whose treatments fall below the professional standards and cause harm to patients may be held civilly liable for that failure.⁴³ Various ways have been proposed that ensure individuals going into research protocols are giving informed consent, these include: written and oral forms of consent so that the donor or donor proxy has time to read and reflect on the risks and benefits; someone other than a member of the surgical team obtains the informed consent; obtaining second opinions from other knowledgeable physicians regarding the feasibility of such a procedure; and appointing an objective advocate who would accompany the donor or donor proxy during the decision-making process. These advocates would ensure that the information is relayed to the donor or donor proxy “in a comprehensive, compassionate and even-handed manner.”⁴⁴ These are not only excellent safeguards; they should be implemented with every donation protocol.

Medical advances are necessary for society, and experimental donation procedures are important tools to bring about these advances. But these advances can never be at the expense of denying individuals their basic dignity and respect. If donors or donor proxies are made aware and comprehend the success data, short-term and long-term risks and benefits, alternatives and possible consequences and safeguards are put in place to avoid the potential for coercion, then informed consent can be obtained ethically for the NRP procedure.

Beneficence/Nonmaleficence

Beneficence involves the obligation to prevent and remove harm and to promote the good of the person by minimizing the possible harms or risks and maximizing the potential benefits. Beneficence includes nonmaleficence, which prohibits the infliction of harm, injury, or death upon others. In medical ethics this principle has been closely associated with the maxim Primum non nocere: “Above all do no harm.”

NRP is a promising new development in the field of organ transplantation, especially for heart donations, because hearts are difficult to procure by the standard DCD donation.  Proponents argue that NRP can increase the number of organs available for transplant and increase the quality of organs by keeping them more perfused. “The number of organs would likely be increased by enabling the transplantable organs to be resuscitated in situ, such that otherwise unusable organs could become transplantable. In situ resuscitation has the potential to increase the function and the quality of the organs before they are removed for transplantation, which would improve graft function and survival in the long run.”⁴⁵ NRP is a modification of the standard DCD donation, which has been in use since 1992, and which is now a well-accepted approach to organ procurement.  Proponents further argue that NRP does not violate the DDR because the restoration of circulation is only regional (excluding the brain in TA-NRP, and excluding the brain and thoracic organs in A-NRP), and consider the fact that circulation is restored in situ rather than ex vivo to be ethically irrelevant.⁴⁶ Opponents to NRP argue that this procedure has the potential to violate the Dead Donor Rule, which is the foundation stone of organ transplantation. “Abdominal NRP (A-NRP) involves perfusing (providing blood flow to) the liver, kidney and pancreas and other tissue in the lower part of the body using the tube inserted below the diaphragm, either into the iliac artery and vein or into the abdominal aorta. Thoracoabdominal NRP (TA-NRP) involves perfusing the thoracic organs in addition to abdominal ones, and includes blood flow through the heart; both forms of NRP involve occlusion (blocking blood flow to) arteries to the brain.”⁴⁷  The Dead Donor Rule clearly states that the donor must meet the criteria for death at the time of donation, to verify that the donor does not die by or for donation. Opponents argue that NRP “raises questions about whether the act of ligating the arteries or using an occluding balloon prior to perfusion with the knowledge and intent of restarting regional circulation constitutes a violation of the Dead Donor Rule, as well as a violation of the UDDA, by rendering the initial determination of death by circulatory criteria invalid (as circulation was restarted successfully), and without a determination of death by brain death criteria.”⁴⁸ It appears the declaration of death is voided when the grounds for the declaration are negated by subsequent action. This would violate the principle of nonmaleficence-do no harm.

Before NRP begins, the donor must legitimately meet the criteria for determining death. The criteria for the Dead Donor Rule has been met.  To avoid any misinformation about the procedure, it is advisable that a member of the OPO be available to the donor or donor proxy to accurately and fully answer any questions about the organ donation recovery process.  There must be a standardized protocol used in the disclosure of information which supports authorization of the organ donation process in an informed manner.  There must be complete transparency about the procedure and the process of recirculation of blood for the perfusion of the organs.  What we want to avoid is providing the donor or donor proxy with any conflicting information during this time of grief so as to not create more pain or grief.  The donor and donor proxy must be informed about the criteria for death, the declaration of death, and the use of machines to circulate blood after death. This is the only way that transparency will be assured.  We also advocate for additional research confirming that protocols being deployed preclude any question that the donor meets the criteria of the Dead Donor Rule. No one will dispute that balancing the benefits and risks is difficult. Some will continue to argue that the risks outweigh the benefits. However, as long as the donor and donor proxy has informed consent and understand the artificial establishment of circulation after the declaration of natural death, their intention is to donate organs and they understand the intention of NRP, then they have the right to agree to this procedure. For many individuals, their desire to be an organ donor clearly outweighs the possible medical risks to them. Arguably, it appears that NRP does not fail the test of beneficence or the test of nonmaleficence. 

NRP has the potential of saving many lives because of the ability to harvest more usable organs. It has the potential to decrease post-transplant morbidity and to provide comfort to many donor families.   These benefits can be negated if the donor or donor families do not understand NRP or have misunderstandings about the process, which could lead to more grief, more psychosocial distress and an increase in public trust. This loss of trust could impact organ donation on a national level. To overcome these negatives, more research must be done in this area. Clinicians must be more transparent about the process and verify that donors or donor proxies give informed consent. This can be accomplished by clear requirements and guidelines for explaining the NRP process, explaining the ethically relevant components of NRP and being consistent in the informed consent process. At the present time, if NRP is being shown to be an effective way organ procurement, and the risk-benefit ratio is reasonable, and safeguards are put in place to assure donor and donor proxies have informed consent, then NRP meets the ethical requirements of respect for person, beneficence and nonmaleficence.

Recommendations & Conclusion

In light of these perspectives and after considering the issue holistically, we are in favor of NRP as a viable and ethical procedure so long as a patient is first clearly and definitively declared dead by DCD criteria according to the Dead Donor Rule. We believe this because after a donor is declared dead by medically accepted standards, the focus of organ transplantation shifts from donor to recipient. However, we will herein propose several recommendations regarding the implementation and practice of NRP in organ transplantation to ensure that the procedure is effective, standardized, and made known to patients, their families, and the public as a whole.

First, more research and data is necessary in order to further contextualize the effects of NRP, particularly as it pertains to heart transplantation. Research topics should include organ outcomes after NRP-based transplantation, NRP’s effect on organ availability, and NRP’s potential to increase donation from Expanded Criteria Donors, or donors who may not satisfy all typical donor criteria but may be eligible if certain parameters were relaxed.⁴⁹ Additionally, the NRP protocol should be examined in lung transplantation to see if the protocol can be applied to increase lung availability as well.⁵⁰ In short, as with any newer, more cutting-edge medical procedure, we recommend that NRP be studied thoroughly to ensure that its implementation more widely is providing patients with evidence-based benefits.

Second, in order to standardize the procedure for widespread implementation, we propose Penn Medicine’s protocol to serve as a paradigm for other programs throughout the country. We chose Penn because it began NRP procedures in 2022 for liver transplantation and because it is among the most experienced transplant centers in the country.⁵¹ We regard Penn Medicine as a leader in the field and consider their expertise to be essential to making a standardized protocol.

Our final recommendation centers on informed consent and transparency. We believe that the current process for consenting to organ donation should remain unchanged. Specifically, we do not think that separate consent for NRP is necessary, as agreeing to be an organ donor implies consent to all medically accepted procedures for organ procurement. However, while family and loved ones are notified by the organ procurement organization when NRP is being used, there is no standardized procedure for how this conversation takes place or how well the family understands the situation. Thus, we primarily recommend implementing a standardized procedure for transparency regarding NRP for donors and their families. Informed consent techniques such as the teach-back method can be an effective method to improve these conversations.

Although consent for organ donation is already given, we feel that increasing transparency around this somewhat controversial procedure can have long-term, expansive benefits. Patients will gain a clearer understanding of what happens to their bodies after death, and families will be reassured their loved one’s wishes are being carried out safely and respectfully. Normalizing this controversial procedure along with this increased transparency will lead to greater trust in the medical system and organ transplantation specifically, potentially resulting in more individuals choosing to become organ donors in the future. Conversely, we fear that a lack of transparency regarding NRP could have the opposite effect, further eroding public trust in medicine if people feel that this procedure has been obscured from public knowledge.

If nothing else, the perspectives presented in this paper reveal that the conversation on NRP is complex, interprofessional, and necessary. And while our recommendation calls for the broader implementation of NRP so long as DDR and informed consent are satisfied, we recognize that, as with any ethical issue, the discourse must continue and be reevaluated frequently as new research and outcomes emerge. It is our hope that transplant centers across the country consider what has been proposed in this paper and consider the potential of NRP.