Prolonging Ex Vivo Lung Perfusion (EVLP)

Despite the widespread use of EVLP, translation into an increased number of lung transplants remains modest. One aspect that may be limiting better recovery of lungs is the fairly short perfusion time. Decisions are often made within a few hours, and even the most enthusiastic proponents have not done more than 12-hour perfusions.

To explore the feasibility of prolonging EVLP to 24 hours, the Toronto group⁽³⁾ conducted pig experiments with three alterations to the perfusate: continuous replacement of the perfusate, better control of glucose and the addition of a parenteral nutrition. This last begins to address some of the disadvantages of ex-vivo perfusion, where the lungs are not usually nourished and the lack of systemic circulation means homeostasis is not supported.

They achieved a much higher level of successful 24-hour perfusion when modifications were made to the perfusate than with their standard approach. They suggest this may allow more complex and prolonged therapeutic intervention.

A much greater extension of EVLP time was achieved by the group from Columbia, New York⁽⁴⁾. Using a pig as a support animal, with a pump-driven circulation and external ventilation, they were able to support lungs in a very stable condition for four days. They argue that the homeostasis allowed by connecting to a systemic circulation is essential for good repair of the lung.

Then, in one of the most innovative and daring approaches to EVLP which has yet been published⁽⁵⁾, they extended this concept of the support animal. In a series of lengthy experiments, they attached six human lungs, all significantly injured and turned down for transplant, to a pig support animal, in a xenogeneic cross-circulation.
The lungs showed significant recovery, both functionally and histologically, as early as 24 hours, and all maintained a stable perfusion out to four days. The paper supports the advantages of a systemic circulation first shown in the pig-to-pig perfusions, and the fact that this also encouraged repair of injury typically found in the organ donor is impressive.

However, as an accompanying commentary underlines⁽⁶⁾, there are some unsolved and potentially insoluble disadvantages of this model. The xeno-immune aspects had to be controlled by formidable immunosuppression of the host pigs, and blockage of complement activation. Perhaps more importantly, the sort of repair modalities for which an isolated circulation in conventional EVLP are well suited, with exposure of only the donor lung to the intervention, are not possible if there is a whole body attached to the lung. The cross-circulation is very exciting, but it is far from the whole answer.

References:

3. Takashima M, Cheung H Y A, Watanabe T, Liu M, Keshavjee S, et al, Strategies to prolong homeostasis of ex vivo perfused lungs. J Thorac Cardiovasc Surg 2020 Aug 13;S0022-5223(20)32356-4. (online ahead of print) (link to abstract)

4. Hozain, A. E. et al. J. Multiday maintenance of extracorporeal lungs usingcross-circulation with conscious swine Thorac. Cardiovasc. Surg. 159, 1640–1653.e18 (2020). (link to abstract)

5. Hozain, A. E. et al. Xenogeneic cross-circulation for extracorporeal recovery of injured human lungs. Nat Med. https://doi.org/10.1038/s41591-020-0971-8 (2020). (link to abstract)

6. Fisher, A.J., Dark, J.H. Ex vivo repair of human donor lungs for transplantation. Nat Med 26, 1015–1016 (2020). https://doi.org/10.1038/s41591-020-0967-4 (link to extract)

XVIVO Insights PB-2020-10-28