As focus remains on organ preservation, normothermic regional perfusion takes spotlight
Click Here to Manage Email Alerts
Transplant specialist Beatrice P. Concepcion, MD, sees use of normothermic regional perfusion as another tool in the physician’s bag to help secure a healthy organ for transplant. But sources said the technique is not without controversy.
“Early reports on outcomes with normothermic regional perfusion (NRP) have been encouraging,” Concepcion, medical director of the kidney and pancreas transplant program at UChicago Medicine, told Healio | Nephrology News & Issues. “In heart and liver transplantation, it has allowed for recovery and utilization of donation after cardiac death (DCD) organs and expansion of the donor pool.
Source: Beatrice P. Concepcion, MD
“In kidney transplantation, although DCD kidneys are routinely utilized with standard preservation techniques, these kidneys remain at increased risk for delayed graft function (DGF),” she said.
According to sources, NRP is conducted in abdominal or thoracic organs in the body of a donor after declaration of circulatory death; cerebral arteries are clamped and vented to prevent brain perfusion. The technique “is aimed at improving organ quality by reducing cold ischemic time through recirculating oxygenated blood in the donor body before organ recovery and transplantation,” according to a white paper on NRP released by the Organ Procurement Transplant Network (OPTN) Ethics Committee in 2023.
Early results
Use of NRP has led to ethical concerns partly because of a lack of a standard protocol for the procedure and a lack of long-term outcomes on graft survival. In one study, Alice L. Zhou, MD, and colleagues reported outcomes of kidney transplants performed using DCD donor grafts perfused with thoracoabdominal (TA) NRP after circulatory death. Of the 16,140 DCD kidney transplants performed during the study period, 306 (1.9%) used TA-NRP and had lower likelihood of delayed graft function in the study.
“Our results demonstrate that kidney transplants using TA-NRP DCD allografts have positive short-term mortality and graft survival outcomes, with significantly decreased rates of delayed graft function compared with direct recovery DCD grafts,” the authors wrote.
A paper published in Transplantation by Anji E. Wall, MD, and colleagues showed that kidney patients had lower delayed graft function when TA-NRP was used. Although long-term outcomes need to be investigated, “we believe that TA-NRP is an effective approach to expand the use of DCD organs,” the authors wrote.
Ethical concerns
The American Society of Transplant Surgeons (ASTS) and the OPTN have released statements endorsing use of NRP but warn of ethical considerations because the procedure restores circulation to the donor after declaration of death.
“Although enthusiastically endorsed by many as an approach to procuring more and higher quality organs, [NRP] has also drawn criticism, including concerns that it may violate the ‘dead donor rule,’ a fundamental ethical principle of organ procurement that prohibits procedures that may result in patients dying either by or for the procurement of their organs,” Robert D. Truog, MD, of the Center for Bioethics at Harvard Medical School, and colleagues wrote in an editorial published in JAMA.
Despite the concerns, Truog and colleagues wrote the procedure “offers an unprecedented opportunity to improve both the number and quality of organs procured from donation after circulatory death.
“Faced with a growing waiting list, a commitment to saving as many lives as possible, and increasing scrutiny and regulatory pressures, many in the transplant community are eager to embrace [NRP],” they wrote.
Laura Hickman, MD, an assistant professor of surgery in the division of kidney and pancreas transplant at Vanderbilt University Medical Center in Nashville, told Healio | Nephrology News & Issues that NRP can reverses the damage caused by warm ischemia. “I get excited when I receive an NRP [organ] offer,” Hickman said. “I think the OPTN Ethics Committee got it right; this technique has promise, but there are some important questions that we need to answer.”
Hickman has seen in her experience as a transplant surgeon that kidneys from donation of organs after circulatory death perform better when NRP is used vs. standard rapid DCD recovery. “As a surgeon, I look at organs and what they will do over the next week, the next month, the next year,” Hickman said. “With NRP, we are reversing some of the negative effects of ischemia while the organs are still inside the donor’s body – thus they start working sooner after transplant.”
More research needed
In its white paper, the OPTN Ethics Committee agreed with Truog and colleagues that NRP raises concerns about compliance with the dead donor rule, writing “ ... a person may legitimately meet criteria for determining death owing to permanent cessation of circulation at the time of death declaration, but that this criterion is subsequently violated when circulation is restored” by NRP. The committee also wrote that assurances were needed that NRP techniques prevented cerebral flow. “Additional evidence is needed to demonstrate that cerebral flow to the brain is minimal,” the committee wrote, adding: “Uncontrolled scenarios for NRP, in which circulatory death occurs unexpectedly and not after the planned withdrawal of life support, raise very serious concerns for respect for persons and proceeding too quickly from therapeutic treatment to organ recovery.”
Likewise, NRP has developed in the United States without a formal, objective ethical evaluation being conducted by the OPTN or otherwise within the transplant community, the committee wrote. “Currently, [organ procurement organizations] OPOs and transplant programs use a patchwork of varied approaches and decision making when it comes to NRP, which may represent inconsistencies within the transplant system.”
Concepcion said more research is needed to show the effectiveness of NRP.
“We need organ-specific data to show that it reduces DGF and improves clinical outcomes, reduces discards and data to show its cost-effectiveness,” Concepcion said.
‘Saves lives’
In its consensus statement on NRP, developed by a panel of experts in June 2023, the ASTS wrote it “recognizes that there are ethical considerations regarding NRP procedures but feels strongly that NRP saves lives and offers an ethically sound donation modality that does not violate essential moral, philosophical or bioethical principles.
“NRP must be implemented in a way that maximizes the number of patient life-years saved and follows the highest ethical standards,” the ASTS wrote.
The precautions do not quell the concerns about defining circulatory death, Jonah Rubin, MD, a critical care physician and pulmonologist in the division of pulmonary and critical care medicine at Massachusetts General Hospital and Harvard Medical School, wrote in an editorial titled, “The irreversible cannot be reversed: Normothermic regional perfusion is euthanasia,” in the Journal of Cardiothoracic and Vascular Anesthesia.
“[The Uniform Declaration of Death Act] defines cardiac death as ‘the irreversible cessation of circulatory and respiratory functions.’ With thoracoabdominal NRP, circulatory function is restored. The heart beats again sufficiently to even permit extracorporeal membrane oxygenation decannulation,” Rubin wrote.
“No wordsmithing or philosophical acrobatics negates this simple truth.”
In an interview with Healio | Nephrology News & Issues, Rubin said he is not completely in favor of banning use of the procedure.
“My key issue with NRP is that we declare death (if not brain death) on the basis of the Uniform Declaration of Death Act definition — ‘irreversible cessation of circulatory and respiratory function’ — and then proceed to reverse circulatory function,” Rubin said. “Proponents of NRP tend to hinge on the fact that death was ‘declared’ and ignore the fact that this declaration was made based on a criterion proved incorrect. Death can be misdiagnosed.”
While Rubin acknowledged in his editorial that using NRP is directed at helping patients in need — “Although in the noble context of organ donation from a dying patient, many could understandably justify NRP” — he wrote, “ ... euthanasia under any circumstances remains a line this country has not, and should not, cross. Certainly, no individuals or institutions should be empowered to proceed before achieving broad societal consensus.”
“I completely understand the appeal of NRP and believe the intentions of proponents of NRP are noble and well placed,” Rubin told Healio | Nephrology News & Issues. “I also don’t necessarily believe that NRP is immoral or unethical at least from the patient’s perspective; if a patient is dying, care is going to be withdrawn regardless, and they are going to donate organs.
“ ... If we as a society can agree on an updated definition, a challenging task which would require a definition that captures everyone that we agree to be dead, and also somehow will include patients in the state they are in during NRP but does not unduly include people we do not agree are dead — then all problems here are solved.”
Hickman agreed it is time for a more structured approach to using NRP, including techniques that insure perfusion does not reach the brain. “Clamping the brachiocephalic (artery) is the standard technique I have seen and occludes the major and second most major blood vessels to the brain,” Hickman said. “But there are some studies in the neurology literature that the blood vessels that go to your spinal cord can also feed your brain stem or posterior brain.
“But the papers written on this topic have said, ‘We don’t know how much’ and ‘is it significant enough’ to mean anything if NRP is performed,” she said. “I think as a profession we need to address this. That will require some rigorous studies.”
The value of NRP in protecting the quality of donated organs comes at a time when transplant centers reject a high percentage of organs as unusable, Concepcion said. “Given the high DGF rates we have right now, and which are only bound to increase as we push to utilize more DCD kidneys, interventions that can minimize DGF or shorten its duration can provide tremendous value,” Concepcion, an associate editor for Healio | Nephrology News & Issues, said. “Prolonged DGF is tough on patients, caregivers and the health care team, and alleviating that would not only potentially improve outcomes and quality of life but also increase utilization of kidneys that would otherwise be discarded.”
- References:
- Fox C, et al. Ethical analysis of normothermic regional perfusion (NRP). https://optn.transplant.hrsa.gov/policies-bylaws/public-comment/ethical-analysis-of-normothermic-regional-perfusion/. Accessed April 22, 2024.
- Rubin J. J Cardiothorac Vasc Anesth. 2023;doi:10.1053/j.jvca.2023.12.011.
- Truog RD, et al. JAMA. 2023;doi:10.1001/jama.2023.9294.
- Wall AE, et al. Am J Transplant. 2023;doi: 10.1016/j.ajt.2023.04.021.
- Wall AE, et al. Transplantation. 2024;doi:10.1097/TP.0000000000004894.
- Zhou AL, et al. Transplantation. 2024; doi:10.1097/TP.0000000000004801.
- For more information:
- Beatrice P. Concepcion, MD, can be reached at beatrice.concepcion@bsd.uchicago.edu.
- Laura Hickman, MD, can be reached at laura.a.hickman@vumc.org.
- Jonah Rubin, MD, can be reached at jrubin5@mgh.harvard.edu.
Collapse
Read more about
Click Here to Manage Email Alerts