Background

Heart transplantation has proven to be lifesaving for thousands of patients with advanced heart failure since its inception in 1967. Despite our advances, this procedure is performed less than 6000 times a year worldwide¹ and many hundreds of listed patients and thousands of unlisted ones die every year awaiting a transplant. The biggest obstacle limiting expansion of heart transplants is the same one limiting transplantation of other organs: demand far exceeds supply. Hearts are significantly more challenging to attain than other organs because hearts have historically been derived almost exclusively from brain-dead donors (also referred to as Donation after Neurological Death, or DND).

Donation After Circulatory Death

The decision to withdraw life-sustaining therapies (WLST) ensues after determining that further treatment will not enable survival, nor will it produce a functional outcome with acceptable quality of life to that patient². If the patient’s medical decision maker agrees to organ donation, donation may occur after compassionate extubation if death by circulatory criteria (ie., cardio-pulmonary arrest) occurs within a previously established timeframe. Controlled donation after circulatory death (cDCD) involves declaration of death after a “hands-off” 5-minute waiting period during which it is ensured that cardiac activity does not spontaneously recur, followed by organ procurement.  Of note, a recent international prospective study of 480 patients demonstrated that no patients had circulation beyond 5 minutes, and all patients progressed to death³. Currently, cDCD is practiced in 17 countries: Australia, Austria, Belgium, Canada, China, Czech Republic, France, Ireland, Italy, the Netherlands, New Zealand, Norway, Spain, Sweden, Switzerland, the United Kingdom, and the United States.²

Heart Transplantation After cDCD

Two newer techniques that allow for heart transplantation following cDCD currently in use are: Direct Procurement and Perfusion (DPP) or Thoraco-Abdominal Normothermic Regional Perfusion (TA-NRP).

Direct Procurement and Perfusion (DPP)

In DPP, following declaration of death after the “hands-off” period, the heart is removed, instrumented, and placed into a perfusion device.⁴ While this device can measure arterial and venous lactate levels, it is incapable of assessing the mechanical function of the heart. It is unknown if the donor heart, which has now undergone a period of warm ischemia, instrumentation, and machine perfusion, can maintain circulation in the recipient until after the transplant¹. Hearts procured in this manner are frequently rejected based on their lactate profile, even if usable, and carry a high cost, with the machine costing $270,000 and each perfusion costing an additional $68,800⁵.  Outcomes from heart transplants using this procurement method have been shown to be similar to those of DBD.⁶

Normothermic Regional Perfusion

In Normothermic Regional Perfusion (NRP), upon declaration of death by circulatory criteria following the “hands-off” period, the patient is instrumented, and Extra-Corporeal Machine Oxygenation (ECMO) is started. There are two forms of NRP: Abdominal NRP (A-NRP), where the thoracic aorta is cross-clamped and ECMO started via femoral access to allow for abdominal organ perfusion, and Thoraco-Abdominal NRP (TA-NRP), where the cerebral vessels are either ligated or drained following sternotomy, and the great vessels are cannulated for ECMO to allow for cardiac perfusion. The heart typically restarts following ECMO, allowing for the mechanical evaluation of the heart via direct visualization, transesophageal echocardiography (TEE), and pulmonary artery catheterization prior to transplantation. This technology has already demonstrated an increase in the number of heart transplants compared to baseline, with outcomes comparable to DBD heart transplants.^7,8

Despite the ligature of the cerebral vessels, the presence of anastomoses via one of several pathways may continue to perfuse areas of the brain and brainstem after both A- and TA-NRP. These include a) thoracic aorta to posterior intercostal to anterior spinal artery; b) inferior epigastric to internal thoracic to subclavian to vertebral arteries; c) thoracic aorta to supreme intercostal to costo-cervical trunk to subclavian to vertebral arteries; and d) thyrocervical trunk to ascending cervical to vertebrobasilar arteries⁹. In a porcine model of NRP, one out of five animals demonstrated collateralization of flow to the brain, though without return of brainstem reflexes nor increase in activity on BiSpectral Index (BIS), electroencephalogram (EEG), or Near-Infrared Spectroscopy (NIRS) monitoring¹⁰. Testing to assess for the possibility of preserved cerebral perfusion, as is recommended by the European Society for Organ Transplantation, is currently performed in some countries, though not in the US. It is unclear if this technology is sensitive enough to detect small amounts of persistent brainstem flow¹¹ or what the significance of this flow is.

While already performed in many countries, including Belgium, Spain, Italy, the Netherlands, France, and some centers in the United States, TA-NRP is not currently performed in Australia or Canada¹¹. The UK, where this technique was developed, has currently paused NRP pending additional research, and a recent exploration of NRP in Canada concluded that while DPP aligns with its current guidelines, NRP requires further work to ensure the absence of brain perfusion.^12,13 

Ethical Principles Guiding Organ Donation

The Dead Donor Rule (DDR) is the main ethical principle guiding organ donation in the United States. The DDR states that “a vital organ cannot be removed until the donor is determined to be dead according to medical standards and legal criteria” and “removing a vital organ cannot cause the death of the donor.”¹⁴ The DDR cannot be overridden by an autonomous decision. Thus, even a person’s voluntary sacrifice to save another is not considered ethically or morally justifiable.

Ethical Concerns Over TA-NRP

The main ethical concern over TA-NRP is in regard to the Uniform Determination of Death Act (UDDA). The UDDA is the legal basis for death pronouncement in the United States, stating that “[a]n 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.” If the basis for the determination of death during DCD is “irreversible cessation of circulatory and respiratory functions”, then restoration of circulation upon initiation of ECMO in TA-NRP may invalidate the death declaration.  If the patient’s death declaration were annulled, organ procurement would then constitute a violation of the DDR.

TA-NRP proponents argue that the absence of brain flow by ligation of cerebral arteries maintains a persistent state of death under neurologic criteria, even if the patient's circulation has been restored¹⁴. When exploring the justifications used to define brain death as human death in 2008, the US President’s Council on Bioethics agreed upon the unifying medical concept of death by majority decision¹⁵. This concept states that death, rather than being an irreversible process, is the permanent termination of brain functions. Proponents therefore argue that the UDDA should not be interpreted literally² and the patient remains dead because total or near total permanent brain destruction is the unavoidable result of cDCD, whether with or without TA-NRP.

A counterargument invokes the principle of double effect which states that an action that causes an adverse effect is ethically and morally justifiable if it is meant to provide benefit. WLST is acceptable when the goal is to provide benefit by respecting the patient’s autonomy and alleviate suffering - even if the withdrawal is likely to cause the patient to die - as long as death is not the intended result. Instead, if an activity is intended to cause death, it is equivalent to euthanasia and is unethical. If the patient’s declaration of death is invalidated by the restoration of circulation, then the cerebral vessel ligature in TA-NRP represents an intentional attempt to cause brain death¹⁴.

Another major ethical concern lies in the possibility of ongoing cerebral perfusion through collaterals. Even though the European Society for Organ Transplantation guidelines recommend monitoring cerebral perfusion via NIRS, BIS, or EEG¹¹, these technologies may not be sensitive enough to monitor for the presence of brainstem perfusion. In a study of 3 patients undergoing TA-NRP, 1 patient had approximately 50 mL/min of blood draining from the open distal ends of the cerebral vessels. Though this is far less than the 10-12 mL/100 g brain tissue/min that would be necessary to maintain neuronal membrane integrity and function, the authors conclude that “…TA-NRP … cannot be considered to provide absolute reassurance of the complete absence of brain blood flow or perfusion”⁹. Because the brainstem may have retained perfusion, albeit minimal, it remains uncertain if the donor can experience suffering or awareness. Newer techniques aimed at reducing this anastomotic cerebral blood flow that involve leaving the aortic arch vessels open to drainage or to negative pressure have been devised, but are challenging, time-consuming, and complex⁹.

While TA-NRP is already practiced in the United States, several medical societies have voiced concerns over its practice^16,17. 

Ethical Principles vis-a-vis TA-NRP

The main ethical principles that guide medical care remain Autonomy, Beneficence, Non-Maleficence, and Justice.

Autonomy represents respect for a person and the right to self-determination. While the patient in these instances has no say in their own self-determination - the decision to proceed with TA-NRP lies in their medical decision maker – the goal to respect that person’s wishes persists. While TA-NRP would allow for the maximization of organs donated and thus respect the donor’s desire to help others and their right to self-determination, the principle of double effect would arguably place TA-NRP in direct odds with their right to self-determination. Critical for respect of autonomy is also a clear informed consent process, full transparency in regard to pre- and post-mortem interventions, and the possibility of restoration of cerebral blood flow.

Beneficence denotes the obligation to act in the best interest of the patient. In the case of TA-NRP, the patient’s medical decision maker has determined that WLST is in the patient’s best interest. The team’s responsibility lies in continuing to provide care prior to organ procurement. TA-NRP allows for the maximization of benefit to others by donating organs that would otherwise not be able to be transplanted. NRP would allow for increased availability of hearts that may otherwise not have been able to be transplanted. The lower cost associated with TA-NRP compared to DPP will increase access to hearts for transplantation and make it available in resource-restrained areas.

Non-maleficence, or “do no harm,” is discussed as ante- and post-mortem interventions. In Spain, femoral ECMO cannulation is allowed ante-mortem. This practice is not permitted in the UK or the US. Initiation of a heparin infusion ante-mortem can help with organ preservation and is considered ethically acceptable as the potential ill effects of the intervention causing death are not intended (principle of double effect). The main post-mortem concern is that of direct injury and harm to the patient. If the persistent cerebral perfusion via collaterals were sufficient to allow the donor to be aware or experience suffering during organ procurement, it would be ethically unjustifiable to continue the organ procurement process with TA-NRP. For this reason, the European Society for Transplantation has recommended that brain flow monitoring be utilized with a pre-established plan to abort the TA-NRP process if any such flow is detected¹¹.

Justice represents the concept of fair and equitable distribution of resources as well as respect for the law. TA-NRP requires equitable distribution of benefits and burdens. The ACP has raised concerns that TA-NRP will disproportionately affect stigmatized populations, though this is not unique to TA-NRP but rather applies to all DCD and DBD donors. The respect of autonomy via the informed consent process is critical to maintain justice, as is the ongoing fair allocation of organs. The ongoing ethical dilemma of death declaration surrounding TA-NRP, where TA-NRP may “bring about” death by restoring the circulation and then ligature of the cerebral vessels, are of potential concern for future litigation. Institutions should abide by their local and state regulations.

Conclusion

TA-NRP presents a true ethical conundrum, driven by the variable interpretation of the UDDA and the prospect of persistent cerebral blood flow. DPP is less ethically controversial but leads to fewer transplants due to its associated higher cost. This piece has highlighted these major ethical controversies and applied an ethical framework for its consideration. Neurocritical Care Society members are likely to encounter TA-NRP in their local institutions and are particularly adept at understanding the ethical and moral implications of this practice. Neurocritical Care Society members should be informed about TA-NRP and local practices in order to help guide further conversations within their institutions.