Thursday, April 29, 2010

Ex Vivo Lung Perfusion Renders Previously Unacceptable Lungs Usable

I've had the pleasure of visiting the labs in Toronto where this groundbreaking research is taking place and the results as described here offer great promise in having a global impact, with the potential to double the number of lungs available for transplant. Here is a video describing the EX Vivo Lung system:

By Caroline Helwick Medscape Pulmonary Medicine

April 28, 2010 (Chicago, Illinois) — Assessment and reconditioning of extended or initially rejected donor lungs using ex vivo lung perfusion (EVLP) is safe and leads to favorable outcomes after transplantation, according to results from the HELP trial — the largest clinical experience of EVLP to date — conducted at the University of Toronto in Ontario.

The trial results were presented here at the International Society for Heart & Lung Transplantation 30th Anniversary Meeting. The study employed the normothermic acellular Toronto XVIVO system (Vitrolife). "In the HELP trial, we aimed to determine the safety of transplanting initially rejected donor lungs after ex vivo re-assessment and reconditioning," said principal investigator Marcelo Cypel, MD, from the Toronto Lung Transplant Program of the University of Toronto, who presented the results.

The early outcomes of transplant after EVLP are at least equivalent to those using conventionally assessed and preserved donor lungs, said Dr. Cypel.

"Worldwide, only about 15% of donor lungs are accepted for transplantation. EVLP is a new technique that allows time to accurately assess the lung and to optimize function of injured donor lungs that would otherwise not be used," Dr. Cypel explained.

HELP was a prospective nonrandomized trial that included donor lungs that were considered unacceptable on the basis of current clinical criteria and that met study inclusion criteria. Donors were required to have a partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio of 300 mm Hg or less, or of more than 300 mm Hg with additional donor risk factors (multiple blood transfusions, pulmonary edema, donor cardiac death). Poor oxygenation or poor lung compliance was the primary reason for unsuitability.

The lungs were subjected to EVLP at 37 °C with Steen solution for 4 hours. The assessment of transplantability was made after examining lung function in the system. Organs with a partial pressure of oxygen (pO2)/FiO2 ratio of more than 400 mm Hg during EVLP were transplanted. The primary end point was a primary graft dysfunction (PGD) score of 2 to 3 within 72 hours of transplantation. Secondary end points were 30-day mortality, length of stay in the intensive care unit (ICU), length of stay in the hospital, length of intubation, proportional survival, and biomarkers in perfusate and lung tissue.

Between September 2008 and January 2009, there were 309 donors, and 129 lungs (41%) were used for 136 transplants. Of these, 25 were enrolled in the HELP trial and 22 went to transplant. These patients were compared with 114 conventionally treated control subjects. Of the 22 patients in the EVLP group, 19 had extended criteria — "no EVLP available and transplanted with concerns" — or were outright rejected.

Of the 25 lungs treated with EVLP, 22 improved sufficiently to be transplanted, and all functioned well after transplantation, the investigators reported.

Donor characteristics were similar between the HELP and control groups, except the HELP group had significantly more donors from cardiac deaths, and more patients with abnormal bronchoscopy, lower PaO2, and positive cultures. The donor score was also significantly higher in the HELP group (6 vs 4; P < .0001). Recipient demographics were similar between the groups.

The total preservation time (time to implantation) was 10 hours (range, 6 to 17 hours) for the EVLP group, after which a significant improvement in lung function was observed in the treated organs, Dr. Cypel reported.

In the majority of cases, PGD grade after EVLP was 0 to 1. "A few with good lung function after EVLP had PGD grade 3 upon ICU arrival, but this quickly improved to 0 or 1 within 24 hours," he said. PGD grade 2 was more common in the control group. More than 30% of these patients had PGD grade 2 at 24 hours, compared with 10% of the HELP group. By 72 hours, PGD grade 2 was observed in approximately 25% of the control group and 15% of the HELP group.

 "For recipient outcomes, we saw no significant differences between the HELP population and controls," Dr. Cypel reported. This included 30-day mortality, time to extubation, ICU and hospital length of stay, PaO2/FiO2 ratio upon ICU arrival, and need for extracorporeal mechanical oxygenation.

 Thirty-day mortality was 10.5% in the HELP group and 5.2% for other transplantations. No patients required extracorporeal mechanical oxygenation after EVLP, compared with 3.5% with conventional transplant. At 560 days posttransplant, survival was 80% for each group, he reported.

 "Our system was able to discriminate between the lungs that were acceptable, and therefore transplanted (n = 22), and those that were rejected (n = 3), Dr. Cypel noted. In general, the rejected lungs had lower gas exchange, higher pulmonary vascular resistance, and higher airway pressure. Interestingly, the rejected lungs also had higher levels of inflammatory cytokines, he said.

 "Using the inflammatory chip (Xceed), we are exploring the inflammatory gene profile before and after EVLP, trying to identify what these changes mean," he said. Dr. Cypel added that identification of biological predictors of donor lung quality during EVLP, perhaps through a genetic profile, would be helpful in the evolution of this technology.

Future May Be "Personalized" Organ Transplant

Dr. Cypel's presentation was followed by an invited lecture by Shaf Keshavjee, MD, the F.G. Pearson–R.J. Ginsberg Chair in Thoracic Surgery and director of the Toronto Lung Transplant Program. Dr. Keshavjee was involved in the HELP study, but he expanded upon the study's findings to provide a broader picture of EVLP.

He said that the concept of donor organ management is changing toward a paradigm that focuses on "regeneration, not death" of the organ. "The focus has been on slowing down death, rather than facilitating recovery and regeneration," Dr. Keshavjee said. "Currently, we only find out how the organ works after we implant it."

Currently, assessment of organ function is impossible at procurement, leading to the rejection of questionable organs that might be accepted in the setting of ex vivo evaluation. Going beyond assessment, ex vivo optimization of organs would increase the percentage of transplantable organs, with very few organs rejected in the end, Dr. Keshavjee explained.

"How do we get there? We need to develop a stable, reliable ex vivo maintenance perfusion technique and treatment platform," he said, "and develop a 'treatment arsenal' that is capable of injury-specific repair and immunological preparation for tolerance."

A number of questions remain with regard to organ-specific needs (heart, lung, liver) and approaches, mechanical and engineering factors, perfusate composition, and so forth. "Different resuscitation objectives will require different perfusion strategies," Dr. Keshavjee pointed out.

There are short-term issues, he added, such as thrombolysis and metabolic support, intermediate needs that might be addressed by gene therapy and immunomodulation, and long-term needs that call for regenerative medicine approaches. Functional repair of human donor lungs by interleukin-10 gene therapy has already been reported by the Toronto group, he noted (Sci Transl Med. 2009;1:4ra9).

The HELP study was funded by Vitrolife. Dr. Cypel has disclosed no relevant financial relationships. Dr. Keshavjee reports receiving grants and research support from Vitrolife and Astellas Canada, and holding the Chair in Transplantation Research, which is funded by Wyeth (Pfizer).

International Society for Heart & Lung Transplantation (ISHLT) 30th Anniversary Meeting: Abstract 258. April 23, 2010.

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