Due to the donor shortage in lung transplantation, there is significant interest in ex vivo lung perfusion (EVLP) technologies for evaluating and treating organs that are typically not used for transplant. Okamoto et al1 reviewed their single-center translational laboratory experience in their report entitled “Transplant suitability of rejected human donor lungs with prolonged cold ischemia time in low flow acellular and high flow cellular ex vivo lung perfusion systems.” The following narrative provides a synopsis and perspective on their important research.
There are several important variables in EVLP, including duration of preperfusion cold ischemia and choice of cellular versus acellular perfusates. Cypel et al2 were able to successfully transplant a series of swine lungs exposed to 12 hours of cold ischemia followed by 12 hours of normothermic EVLP using acellular solution. Posttransplant oxygenation throughout 4 hours was excellent. This and other studies inspire the concept of sending marginal lungs to distant perfusion centers on cold ice for further reconditioning and evaluation on EVLP. This has the potential to expand the donor pool by allowing organ procurement networks to leverage these perfusion centers to increase donor yield at minimal inconvenience to the transplanting institution.
Similarly, Spratt et al3 perfused extended criteria donor swine lungs on a portable EVLP circuit after a mean cold ischemic time of 30 minutes. The authors perfused the lungs for 24 hours using autologous whole donor blood before transplantation. They showed acceptable lung compliance and function, although oxygenation was marginal relative to the amount of preoperative donor insult. Of note, the authors showed that prolonged EVLP perfusion (>12 h) required autologous whole blood instead of fresh cell salvage blood which was used to simulate packed red blood cells.4,5
The distinction between acellular and cellular perfusion is important. Theoretically, lung parenchyma requires circulating red blood cells. However, several researchers have suggested that the combination of oxygen through ventilated alveoli combined with a low oxygen demand in the parenchyma allows lungs to survive with acellular perfusion and ventilation.6,7 At present, there are a variety of EVLP systems that utilize either cellular or acellular perfusion with reasonable success in terms of donor organ utilization and function after transplant.
The study of Okamoto et al1 adds to the growing literature with a sophisticated set of experiments utilizing 2 different EVLP systems and human lungs turned down for transplantation. Their efforts required considerable cooperation from their organ procurement network and diligent experimentation in the EVLP laboratory. Sixteen donor lungs were studied in this paper. These lungs were divided evenly between 2 different systems. The first system was the low flow acellular EVLP. This system used the XVIVO chamber (XVIVO Perfusion AB, Goteborg, Sweden), a centrifugal pump, a membrane oxygenator, and STEEN acellular solution (XVIVO Perfusion AB) at 40% of the calculated cardiac output. The second system was a high flow cellular EVLP using Vivoline LS1 (Vivoline Medical AB, Lund, Sweden) with 2 units packed red blood cells at a target flow rate of 70 mL/min/kg.
The high flow cellular system showed a significantly lower PaO2:FiO2 ratio and higher pulmonary vascular resistance than the low flow acellular system. However, the low flow system caused greater edema. The low flow acellular group had higher pathologic scores than the high flow cellular group, suggesting that the blood and flow may have helped reduce tissue damage. Despite the encouraging physiologic performance of these lungs after prolonged cold ischemia and prolonged normothermic preservation, very few were transplantable. Thirty-eight percent of the low flow acellular organs and 0% of the high flow cellular organs were felt to be transplantable by 2 designated authors after gross assessment and consideration of a combination of physiologic variables. Interestingly, in both systems, long versus short cold ischemic times were associated with significant elevations in inflammatory cytokine levels. This suggests that prolonged cold ischemia results in greater inflammation and reperfusion injury.
In summary, the authors suggest that prolonged cold ischemia (>8 h) is associated with significant reperfusion injury in either the EVLP system. But a comparison of the 2 systems suggests that the low flow acellular platform resulted in greater likelihood of transplantation, better physiologic improvement, but more edema. The high flow cellular platform resulted in no organs that would be considered transplantable, but less edema and less damage as assessed by the pathologic scoring method. Both systems showed a significant elevation in inflammatory cytokines after reperfusion.
This study explores characteristics and values of 2 different static EVLP systems and highlights the utility of EVLP as a tool for gauging the extent of reperfusion injury during long ischemic intervals before transplant. Comparisons between systems are very much needed in the literature in order to better tailor the EVLP strategies to the clinical scenario. There are currently 3 commercially available systems including Vivoline (Vivoline Medical AB, Lund, Sweden), XPS (XVIVO Perfusion AB), and Organ Care System (Transmedics, Andover, MA). Studies such as this build on the data comparing different modes of preservation and add considerable value to the evolving science of EVLP. This study underscores the limitations of prolonged cold storage and the potential hazards of transplanting organs after such prolonged ischemic intervals.
1. Okamoto T, Wheeler D, Farver C, et al. Transplant suitability of rejected human donor lungs with prolonged cold ischemia time in low flow acellular and high flow cellular ex vivo lung perfusion systems. Transplantation. In press
2. Cypel M, Yeung JC, Hirayama S, et al. Technique for prolonged normothermic ex vivo lung perfusion. J Heart Lung Transplant. 2008; 27(12):1319–1325
3. Spratt JR, Mattison LM, Iaizzo PA, et al. Lung transplant after prolonged ex vivo lung perfusion: predictors of allograft function in swine. Transpl Int. 2018; 31(12):1405–1417
4. Loor G, Howard BT, Spratt JR, et al. Prolonged EVLP using OCS lung: cellular and acellular perfusates. Transplantation. 2017; 101(10):2303–2311
5. Spratt JR, Mattison LM, Iaizzo PA, et al. The ABCs of autologous blood collection for ex vivo organ preservation. J Thorac Cardiovasc Surg. 2018; 155(1):433–435
6. Egan TM, Requard JJ III.. Uncontrolled donation after circulatory determination of death donors (uDCDDs) as a source of lungs for transplant. Am J Transplant. 2015; 15(8):2031–2036
7. Sanchez PG, Bittle GJ, Burdorf L, et al. State of art: clinical ex vivo lung perfusion: rationale, current status, and future directions. J Heart Lung Transplant. 2012; 31(4):339–348