Increasing Transplantable Donor Lungs through Ex Vivo Lung Perfusion

By Toshihiro Okamoto, MD, PhD, and Kenneth R. McCurry, MD

Cold storage of donor organs following procurement and prior to transplant decreases metabolic demand and consumption of energy and has been the standard method in transplantation for more than 40 years. Severe damage occurs when energy stores are depleted, including increased oxidative stress, inactivation of the sodium pump, cell death, and the release of proinflammatory cytokines. Additionally, following implantation, lungs frequently demonstrate varying degrees of ischemia reperfusion injury (IRI) resulting in postoperative graft dysfunction and complications that have short- and long-term implications. Thus, lung preservation and mitigation of IRI remain two of the main concerns in clinical lung transplantation.

Preventing cold injury with ex vivo

Normothermic ex vivo organ perfusion is based on the rationale that providing oxygen and nutrition at physiologic temperatures on an ex vivo perfusion circuit prior to transplantation can prevent cold injury. Furthermore, it is possible that such ex vivo lung perfusion (EVLP) could be used to recondition and repair dysfunctional lungs after procurement, thus making them transplantable and resulting in an increased number of lungs available for transplantation.

EVLP could prove to be especially beneficial in situations when untransplantable, dysfunctional donor lungs have pulmonary edema or areas that remain atelectatic despite in situ recruitment. In EVLP, the high oncotic pressure of the perfusate draws water from the lung tissue and alveoli into the extra-pulmonary space, reducing pulmonary edema. Atelectasis can be eliminated through strategic ventilation techniques, which include recruitment maneuvers while on EVLP. Importantly, evaluation of donor lung function is possible during EVLP allowing ongoing assessment of lung function in response to therapeutic maneuvers.

Meeting demand through reconditioning

In the U.S., 1,600-1,800 lung transplants are performed annually, with many patients dying prior to an organ(s) becoming available for them. Unfortunately, approximately 80 percent of lungs offered for transplantation cannot be utilized due to poor lung function caused by factors including pulmonary edema and atelectasis.

Based on these numbers, the use of EVLP to recondition dysfunctional lungs could have a dramatic impact on the number of patients whose lives could be saved with lung transplantation. Indeed, EVLP has been clinically available in Canada for several years, and the Toronto Lung Transplant Program has increased their lung transplant volume by approximately 30 percent using this technology. In the U.S., the clinical use of EVLP is in its infancy but holds great promise in those programs that have the resources and clinical expertise to utilize it.

EVLP at Cleveland Clinic

We initiated EVLP research activity at Cleveland Clinic in 2011 in the McCurry lab. Several important questions regarding EVLP have been investigated using more than 50 rejected human lungs and over 30 porcine lungs. One of the most critical questions is the accuracy of evaluation of donor lung suitability for transplantation in EVLP, as this is key for patient safety. Parameters utilized to assess lung function for suitability for transplantation can include gas exchange (PaO2/FiO2), lung compliance, vascular resistance, lung weight and visual findings.

Ex vivo lung perfusion system in the McCurry lab.

Deciding whether perfused lungs are transplantable is frequently challenging, especially when PaO2/FiO2 is in the marginal range of acceptability (around the current threshold of 300 mm Hg). In investigating this question, we identified the following important findings on the assessment of lung function in EVLP.

1. The variability of PaO2/FiO2 during cellular EVLP: Previously, PaO2/FiO2 was utilized in EVLP as a main indicator of oxygenation and considered constant at any FiO2. However, we identified that variability of PaO2/FiO2 exists at different FiO2 (0.21, 0.4 and 1.0) in EVLP. Furthermore, we demonstrated that this variability is significant because the pattern of PaO2/FiO2 at FiO2 of 0.21 < PaO2/FiO2 at FiO2 of 1.0 was associated with significantly better oxygenation, higher pulmonary compliance and lower shunt fraction compared to the pattern of PaO2/FiO2 at FiO2 of 0.21 > PaO2/FiO2 at FiO2 of 1.0 in porcine lungs. This algorithm was consistent in human lungs and has significant implications for appropriately assessing and selecting suitable lungs for transplantation in EVLP.
2. A significant correlation between PaO2/FiO2 and other physiological parameters (airway and vascular parameters): In other novel work, we found that airway parameters (compliance) and vascular parameters (resistance) can be utilized as complementary parameters in the evaluation of lungs in EVLP. Use of these supplementary data improves the accuracy and reliability of lung selection in EVLP.

The relationship between P/F ratio at FiO2 0.21 and P/F ratio at FiO2 of 1.0 in porcine model. A, P/F ratio at three FiO2 in the group of P/F0.21 < P/F1.0 (group 1, n = 8). Seven cases were judged as suitable (black symbols), whereas one case was judged as not suitable (red symbol). B, P/F ratio at 3 FiO2 in the group of P/F0.21 > P/F1.0 (Group 2, n = 8). All eight cases were judged as not suitable. ]

Currently, Cleveland Clinic’s Lung Transplant Program is participating in a clinical trial of EVLP — A Phase 2, Multicenter, Open-Label Study to Measure the Safety of Extending Preservation and Assessment Time of Donor Lungs Using Normothermic Ex Vivo Lung Perfusion and Ventilation (EVLP) as Administered by the Sponsor Using the Toronto EVLP System — sponsored by United Therapeutics (Silver Spring, MD). In this study, donor lungs that are deemed not transplantable are procured and transported to a perfusion facility in Baltimore. During four to six hours of EVLP, lungs are reconditioned and assessed for transplantation suitability. When perfused lungs are judged as transplantable, they are transported to Cleveland Clinic, and lung transplantation is performed. Thus far, our patient survival utilizing this method is 100 percent.

This ability to utilize EVLP has brought other benefits as well. With EVLP as a backup, we can be more aggressive with lung procurement, resulting in conversion of some lungs that we thought needed EVLP into transplantable organs without using EVLP. Between February and September 2016, this has resulted in seven additional patients receiving transplants with 100 percent survival.

Overall, since initiating our clinical EVLP program, we have been able to provide transplantation to approximately 20 percent more patients in 2016 than at this time in 2015. We believe that the ability to offer the life-saving therapy of lung transplantation to more patients will continue to grow as we gain more experience and knowledge.

Dr. Okamoto is staff in the Transplantation Center. Dr. McCurry is Surgical Director of Lung Transplantation.