Further insights on optimal cold
ischemic time before lung transplantation

We have previously highlighted the importance of a moderate period (up to circa 6 hours) of cold ischemia prior to warm ex-vivo lung perfusion (EVLP) to achieve optimal post-transplant outcomes (3, 4,). Clinical data from the NOVEL trial (Arango-Tomas et al (4)) also showed that prolonged cold ischemia prior to EVLP (delayed-EVLP) and for an additional period of up to 5 hours after EVLP had no deleterious effect on post-transplant outcomes.

Outcomes in adults

Recent analyses of the UNOS database have also thrown interesting new light onto the role of predominantly cold graft ischemic times ( > or < 6 hours ). In 2015, Grimm et al (5) trawled the UNOS database to compare transplant outcomes in over 10,000 adult lung allografts, of which circa 30% were exposed to prolonged ischemia exceeding 6 hours. There were no differences in clinical outcome or survival at 1 year (83.6% vs 84.%]; or 5 years (52.5% vs 53.5% ) between the two groups of patients, indicating that outcomes were comparable irrespective of whether ischemia was prolonged ( > 6hrs) or short (< 6hrs).

Outcomes in children

A more recent data-mining analysis of pediatric lung transplant records in the UNOS database (6) concludes that a total graft ischemic time of between 4 and 6 hours was associated with optimal survival outcomes, whereas both shorter and longer ischemia had adverse effects. Furthermore, no association was found between donor geographical distance and recipient mortality.

The study was performed by analysts from Columbus, Ohio (Hayes et al, 2016 (6)) on almost 1,000 patients under the age of 18 transplanted between 1987 and 2013. Because the UNOS Registry does not differentiate cold and warm ischemic times, the authors used geographic distance as a proxy for longer cold ischemic time. They found no association between geographical distance and recipient mortality. These findings thus indicate that prolonged cold ischemia does not appear to be a detrimental factor in the preservation of pediatric lungs.

EVLP and ischemic times beyond 12 hours

The Toronto group (7), who currently have most international experience with EVLP, recently posed the question of whether the additional ischemic time required for EVLP affects outcomes. Because the evaluation of donor lungs using EVLP takes 4–6 hours, preservation times with the addition of EVLP have routinely exceeded 12 hours. They therefore investigated whether a total ischemic time exceeding 12 hours had any detrimental effect on early or late post-transplant outcomes.

Total preservation time (TIT) was defined as the sum of first cold ischaemic time, warm EVLP time, and second cold ischemic time. They compared outcomes for 97 lungs where TIT exceeded 12 hours (not surprisingly, 95% of these had undergone EVLP), with 809 lungs recipients where TIT was < 12 hrs.

Findings revealed that median hospital and intensive-care unit length of stay were similar for both groups, and the same applied to PGD grade 3 at 72 hours. There was also no difference in survival between the two groups as shown on Kaplan-Meier survival curves (p=0·61).

Their important conclusions: “Extension of graft preservation time beyond 12 hours with EVLP does not negatively affect early lung transplantation outcomes. Extension of clinical lung preservation times might allow for more transplantations to be done as a result of improved facilitation and increased flexibility around timing of lung transplantation operations.”

3. Mulloy et al, 2012. Ex vivo rehabilitation of non-heart- beating donor lungs in preclinical porcine model: delayed perfusion results in superior lung function. (Link to abstract)
4. Arango -Tomas et al, 2015. Post EVLP Cold Preservation Period Is Associated With Clinical Outcomes. (Link to abstract)
5. Grimm et al, 2015. Association Between Prolonged Graft Ischemia and Primary Graft Failure or Survival Following Lung Transplantation. (Link to abstract)
6. Hayes et al, 2016. Influence of graft ischemic time and geographic distance between donor and recipient on survival in children after lung transplantation. (Link to abstract)
7. Yeung JC et al, 2017. Outcomes after transplantation of lungs preserved for more than 12 h: a retrospective study. (Link to abstract)

XVIVO Insights. PB-2017-03-16