Q&A: Capabilities, limitations of normothermic regional perfusion for lung transplants

Key takeaways:

• The use of normothermic regional perfusion could injure donor lungs meant for transplantation.
• More research is needed on the impact of this technique on the lungs.

In an effort to help more patients in need of lungs receive a transplant, researchers are considering a technique that pumps blood to a donor’s organs and re-perfuses the lungs, according to a press release.

The name of this technique is normothermic regional perfusion (TA-NRP), and it was recently the subject of a debate held at the International Society for Heart and Lung Transplantation (ISHLT) annual meeting.

During the debate, Pedro Catarino, MD, director of aortic surgery at Cedars-Sinai Medical Center in Los Angeles, and Shaf Keshavjee, MD, MSc, FRCSC, FACS, director of the Toronto Lung Transplant Program, discussed the potential of TA-NRP while also acknowledging that there are some limitations that need to be further researched and ethical disputes that need to be settled.

Healio spoke with Catarino and Keshavjee to learn more about the mechanics behind TA-NRP, outcomes of this technique observed in research and limitations/issues associated with TA-NRP.

Healio: How does TA-NRP work? Does this technique need to be performed within a certain timeframe after a donor’s death?

Pedro Catarino

Catarino: TA-NRP involves connecting the donor to a heart-lung machine in much the same way as a patient undergoing heart surgery. Blood is pumped from the venous side through an oxygenator to the arterial side, thereby providing oxygenated blood to all the organs. This allows the organs to recover from the lack of blood supply during the time when the donor has been declared dead.

The sooner blood flow to the organs is resumed, the better in terms of the eventual quality of the transplanted organ. Each organ has its own tolerance to the lack of blood flow, but it is generally felt safe to transplant all the organs if this time is kept under 30 to 35 minutes.

Healio: This technique could potentially raise the number of patients receiving lung transplants. What are some of the reasons behind low donor lung usage?

Catarino: Lungs have the lowest utilization of all the organs because the lungs are most easily injured while the patient is receiving intensive care. In donation after circulatory death (DCD), there is less opportunity to evaluate, optimize and protect the lungs. TA-NRP may help with the evaluation side of this.

Keshavjee: There has been a lot of variability of how TA-NRP is applied in the U.S. and around the world. While some teams have successfully saved the lungs for lung transplant, others have contributed to further injury to the lungs such that they were rendered un-transplantable.

Healio: Why does Canada have a higher usage of DCD lungs than the U.S.?

Keshavjee: We use a technique called EVLP (ex-vivo lung perfusion), that we developed to assess and treat donor lungs after they are removed from the donor, so we treat them ex vivo, or outside the body. This has been very successful for assessing the safety of lungs such that our successful utilization of DCD lungs is over 40%.

Healio: Are there other techniques for preserving lungs for donation, and how does TA-NRP improve upon those techniques?

Keshavjee: Yes, lungs are preserved with low potassium dextran (LPD) solution and stored at 10°C until implant. This is a strategy we developed in Toronto. The LPD solution is used worldwide, and the 10°C (more recently) is being rapidly adopted.

If the lungs fall below acceptable criteria, we use EVLP to assess and treat lungs to make them suitable for transplant. TA-NRP adds a level of concern in that some lungs that have been treated with TA-NRP become irretrievable. We need to optimize the practice of TA-NRP to maximize both heart and lung preservation and transplantation.

Healio: What are some limitations of TA-NRP that need to be addressed in future research?

Catarino: TA-NRP seems most beneficial to the heart, liver and kidneys, which are all organs with less tolerance to lack of oxygen than the lung. There is some suggestion that if not done optimally, TA-NRP may even injure the lungs, hence the debate at the ISHLT conference. This question is what needs further research — when lungs are injured, why is it, and can that be avoided by technical modification to the TA-NRP?

Because TA-NRP is generally on the rise, it might lead us to look at more lungs, and that is why the ISHLT debate was framed as one of utilization, but this will also need further research.

Healio: What research has been done on TA-NRP? What have been the outcomes?

Catarino: There are two published series from single centers (University of Colorado and NYU Langone) with eight lung transplants each and 100% utilization showing excellent outcomes.

There is also one comparative series using the UNOS database of DCD lungs procured where the heart was being used, which compares lungs procured by TA-NRP (n = 26) with those procured without TA-NRP (n = 53), so-called direct procurement. This study showed no difference in utilization, turn down of organs in the donor or short-term outcomes.

Additionally, there are animal studies. The most comprehensive one is from Toronto, where pigs have been subjected to TA-NRP and their lungs compared with those from direct procurement. There were no differences in numerous indicators of lung quality implying that in ideal circumstances the technique is safe.

Keshavjee: Not enough research has been done on the effect of TA-NRP on the lungs. It is possible that the length of time that it takes for the donor to arrest after withdrawal of life support therapies may affect the gut or other body organs, such that reperfusion of those with TA-NRP may cause more inflammatory injury to the lungs. This all must be studied.

Healio: What is the biggest issue in TA-NRP?

Catarino: The biggest issue in TA-NRP is certainly the ethical debate. The patients are diagnosed as dead due to “irreversible” cessation of their circulatory and respiratory function, in the context of planned withdrawal of life support, and so become donors. TA-NRP resumes a part of the circulation, which some argue is “circulatory function,” and so may contravene the previous diagnosis of death. The term irreversible really means spontaneously or naturally irreversible and a “no-touch” period of observation is undertaken to ensure that there is no spontaneous resumption of the circulation.

I don’t think anyone believes these patients could (or should) be resuscitated, but there are concerns that the transplant community could lose the trust of the public. In mitigation of this, there is complete transparency, and I believe all the families of potential donors are made aware of the resumption of part of the circulation in their loved one’s body and accept this.

Keshavjee: TA-NRP is still not legal or permitted in many countries, so this practice is still being debated.

Catarino: It should also be noted the main reason TA-NRP is sought after is that liver and kidney patient outcomes are so much better, and also possibly heart patient outcomes. Lung utilization may be improved as a side product of this. All of this reduces the cost of transplantation (to society). There are separate machine perfusion options for all the organs, but they are much more costly than TA-NRP, which applies to all the organs.

For more information:

Pedro Catarino, MD, can be reached at pedro.catarino@cshs.org.

Shaf Keshavjee, MD, MSc, FRCSC, FACS, can be reached at shaf.keshavjee@uhn.ca.

References:

• Cain MT, et al. JTCVS Tech. 2023;doi:10.1016/j.xjtc.2023.09.027.
• Can TA-NRP increase the number of patients receiving lung transplants. https://www.ishlt.org/about/news-detail/2024/04/12/can-ta-nrp-increase-the-number-of-patients-receiving-lung-transplants. Published April 12, 2024. Accessed April 12, 2024.
• Chang SH, et al. JHLT Open. 2024;doi:10.1016/j.jhlto.2024.100058.
• Choi K, et al. JTCVS Open. 2023;doi:10.1016/j.xjon.2023.08.014.
• Malas J, et al. J Heart Lung Transplant. 2023;doi:10.1016/j.healun.2023.04.009.
• Ribeiro RVP, et al. JHLT Open. 2023;doi:10.1016/j.jhlto.2023.100009.