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Ex Vivo Lung Perfusion: Where are We ... and What's Next?


Marcelo Cypel MD
Dirk Van Raemdonck MD
Shaf Keshavjee MD

University of Toronto
Toronto, Ontario, Canada


Since the inception of the first successful clinical lung transplantation in Toronto in 1983, very few innovations in the field have garnered such attention and excitement in the lung transplant community as Normothermic Ex vivo Lung Perfusion (EVLP). Stig Steen published his work in 2001 when he used EVLP for short term assessment of function of a DCD lung, which was ultimately successfully used for transplantation [1]. Between 2001 and 2007, many experimental EVLP studies were performed in Europe again with the focus of short term lung evaluation in the DCD context [2,3]. In 2007, our group in Toronto presented, at the ISHLT annual meeting in San Francisco, the first concept and feasibility of prolonged EVLP (12h) in association with an active treatment strategy (IL-10 gene therapy) to repair injured donor lungs ex vivo [4]. Subsequent publications, demonstrated the benefits of having a period of normothermic EVLP during the lung preservation process [5] and a seminal prospective clinical trial demonstrated the feasibility and safety of EVLP to assess and improve function of injured donor lungs or lungs from donors after cardiac death [6]. An explosion of EVLP research has occurred since then, and EVLP became one of the major topics of our annual meetings. As expected, in parallel with this, there has been a heightened interest from industry in related technology with at least four companies producing devices for lung perfusion, each however with different characteristics.

In Toronto, EVLP has been an integral part of our clinical lung transplant program since 2008. In 2012, Health Canada approved this strategy and subsequently the ministry of health started to reimburse our hospital for EVLP costs. In 2013, our lung transplant activities increased by 28% in one year, with EVLP being the major responsible factor for that, considering that our multi-organ donor pool number and characteristics did not change. We now have significant experience with over 110 patients that have received EVLP lungs in Toronto. This group of patients enjoys very low rates of severe PGD, and a 5-year survival of 70% in comparison to 63% in contemporaneous conventional transplants.

Several prospective studies of various EVLP techniques are underway or have been recently completed in Europe and North America. This includes the HELP trial (Toronto; sponsor XVIVO Perfusion), the NOVEL trial (USA; sponsor XVIVO Perfusion), the INSPIRE and EXPAND trial (Europe and USA; sponsor Transmedics), the Develop UK (England; sponsor Vivoline), the Vienna trial (Vienna, sponsor XVIVO), and the Perfusix Trial (USA; sponsor Perfusix). Important differences between these studies besides the different technologies and techniques are the specific indications. While the HELP, NOVEL, Develop UK, Expand, and Perfusix trials include extended criteria lungs, the Inspire and Vienna trial are evaluating the impact of EVLP in standard criteria donor lungs. Some of the preliminary results to date of these studies have been presented at the last ISHLT annual meeting, and in general the results are encouraging - both with respect to the ability to rescue declined lungs as well as to provide improved outcomes after transplantation.

Despite all this significant activity and optimism, many questions still remain unanswered and careful further scientific research and investigation is still needed. To highlight a few, first is the controversy about routine or selective use of EVLP in controlled DCD lungs, and second, the attempt to minimize or avoid cold ischemic time by transporting the organ with machine perfusion rather than having a stationary EVLP system. In regards to the first, robust data from highly committed DCD centers have demonstrated the ability to safely transplant category III DCD without the routine use of EVLP [7]. However, EVLP seems to have an important role in extending utilization of DCD lungs when other concerning situations occur such as a prolonged agonal period or concern regarding donor aspiration. It is certainly a mandatory step with categories I and II DCD donor lungs.

Some have proposed that cold ischemia could be minimized or abolished by perfusing the organ from the donor to recipient hospital [8]. However, there is currently no experimental evidence to support that periods of cold ischemia of several hours before and/or after EVLP lead to deleterious effects. In fact, Mulloy and colleagues demonstrated added benefit of 4h of static cold preservation time before EVLP in comparison to normothermic EVLP without cold ischemia [9]. Our group has recently demonstrated both in large animals and humans that long periods of CIT before or after EVLP in fact does not have an adverse impact in recipient outcomes. Whereas, the partial results of the INSPIRE trial presented at the annual meeting demonstrates a benefit to recipients receiving standard criteria donor lungs that underwent machine perfusion during transportation versus cold ischemia alone, this will not answer whether the minimization of cold ischemic times before EVLP had any impact on observed patient outcomes. The randomized study currently under way in Vienna, where no minimization of the first cold ischemic time (CIT-1) will occur (stationary system) will help to further clarify this question. It is very likely that the "intervention of normothermic EVLP" at some point during the total preservation period is the major driver of donor lung quality improvement that we are seeing.

Finally, with the completion of all these important clinical studies, and an increasing body of experimental studies with EVLP, in the near future we hope to see the initiation of clinical trials with active targeted treatment strategies such as drug or molecular interventions during EVLP come to fruition [10]. This will realize the true potential of EVLP in improving both short and long term outcomes of lung transplantation. ■

Disclosure Statement: Marcelo Cypel MD and Shaf Keshavjee MD are founders of Perfusix. They also have received research support from Xvivo perfusion. Dirk Van Raemdonck is a consultant for Transmedics, Andover, MA. He has received research support from Vitrolife, Göteborg, Sweden and from the Fund for Research-Flanders (G.3C04.99).


References:

  1. Steen, S, et al. (2001). "Transplantation of lungs from a non-heart-beating donor." Lancet 357(9259): 825-829.
  2. Neyrinck, AP, et al. (2006). "Comparative study of donor lung injury in heart-beating versus non-heart-beating donors." Eur J Cardiothorac Surg 30(4): 628-636.
  3. Erasmus ME, et al. (2006). "Normothermic ex vivo lung perfusion of non-heart-beating donor lungs in pigs: from pretransplant function analysis towards a 6-h machine preservation." Transplant Int. 19(7): 589-593.
  4. Cypel M, et al. (2007). "Adenoviral mediated interleukin 10 (ADHIL-10) gene therapy in normothermic ex-vivo lung perfusion." J Heart Lung Transplant 26(2S): S212.
  5. Cypel, M, et al. (2009). "Normothermic ex vivo perfusion prevents lung injury compared to extended cold preservation for transplantation." Am J Transplant 9(10): 2262-2269.
  6. Cypel, M, et al. (2011). "Normothermic ex vivo lung perfusion in clinical lung transplantation." N Engl J Med 364(15): 1431-1440.
  7. Levvey, B. J., et al. (2012). "Excellent clinical outcomes from a national donation-after-determination-of-cardiac-death lung transplant collaborative." Am J Transplant 12(9): 2406-2413.
  8. Warnecke, G et al. (2012) Normothermic perfusion of donor lungs for preservation and assessment with the Organ Care System Lung before bilateral transplantation: a pilot study of 12 patients. Lancet. Nov 24;380(9856):1851-8.
  9. Mulloy, DP, et al. (2012). "Ex vivo rehabilitation of non-heart-beating donor lungs in preclinical porcine model: delayed perfusion results in superior lung function." J Thorac Cardiovasc Surg. 2012 Nov; 144(5):1208-15
  10. Machuca, TN et al. (2013). "Injury-specific ex vivo treatment of the donor lung: pulmonary thrombolysis followed by successful lung transplantation. Am J Respir Crit Care Med. 2013 Oct 1;188(7):878-80



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