Caroline Helwick

April 15, 2011

April 15, 2011 (San Diego, California) — The use of normothermic ex vivo lung perfusion (EVLP) to render suboptimal donor lungs more viable for transplant is yielding clinical outcomes comparable with those obtained with conventionally selected lungs, according to some of the first clinical data to emerge on this new approach. The ultimate purpose of EVLP is to increase the availability of donor lungs.

Canadian investigators reported the 1-year results from the Human Ex Vivo Lung Perfusion (HELP) study, which demonstrated excellent transplant outcomes with high-risk donor lungs that were physiologically stable during 4 hours of ex vivo perfusion, here at the International Society for Heart and Lung Transplantation (ISHLT) 31st Annual Meeting and Scientific Sessions.

"Lung transplantation using donor lungs after protective normothermic EVLP is safe, and 1-year outcomes are similar to conventional lung transplants," reported Marcelo Cypel, MD, from the Toronto Lung Transplant Program at the University of Toronto, Onatrio, Canada, and the principal investigator of HELP.

Survival at 1 year has exceeded 80% in each group, he said in a plenary session presentation.

Concurrent with the presentation at the meeting, results were also published in the April 14 issue of The New England Journal of Medicine. Dr. Cypel presented additional data at the ISHLT meeting.

Rationale for EVLP

EVLP using acellular normothermic perfusate after organ retrieval is a way to assess lung viability.

"More than 80% of donor lungs are potentially injured, and therefore not considered suitable for transplantation. With the use of EVLP, the donor lung can be perfused and repaired in an ex vivo circuit, providing an opportunity to reassess its function prior to transplant," Dr. Cypel explained.

Lungs deemed high risk are perfused and ventilated at body temperature, generally for 4 hours, to mimic physiologic conditions. Dr. Cypel said lungs are considered suitable for transplantation if during EVLP the PO2:FIO2 ratio (ie, partial pressure of oxygen to the fraction of inspired oxygen) is 350 mm Hg or lower, and if there is less than 15% deterioration from baseline levels of 3 key physiological measurements.

"To our knowledge, the use of EVLP in humans has not previously been assessed prospectively and systematically. Clinical experience with EVLP is limited," Dr. Cypel noted.

The clinical EVLP experience to date, using the technique developed at the University of Toronto, totals 94 perfusions and 64 subsequent transplants. About half of these were performed at the University of Toronto.

Study Details

HELP was a single-institution, prospective, nonrandomized, noninferiority trial that compared outcomes in recipients of high-risk donor lungs that underwent EVLP (n = 23) with those in recipients of conventionally assessed lung transplants (n = 116), who served as control patients.

Primary graft dysfunction (PGD) was defined as impaired gas exchange meeting ISHLT criteria for grade 2 or 3 dysfunction (PaO2:FIO2 < 300 mm Hg) in the absence of other causes of impaired gas exchange. The study's primary endpoint was PGD 72 hours after transplantation.

Clinical Outcomes Similar

Twenty of the 23 EVLP lungs showed significant improvement in gas exchange and were transplanted. Three showed worsening lung function and were rejected. The 20 lungs selected for transplantation showed stable or improved radiographic findings during EVLP.

There was no difference in the primary endpoint. In fact, the occurrence of PGD 72 hours after lung transplantation tended to be lower in the recipients of EVLP lungs than in the control patients (15% vs 30.1%; P = .11), although the difference was not significant, Dr. Cypel reported.

None of the recipients in the EVLP group had severe PGD at 72 hours compared with 9.4% of control patients (P = .36), he added.

There was also no significant difference between the groups in the occurrence of PGD on arrival to the intensive care unit and at 24 and 48 hours posttransplantation. None of the patients with EVLP transplants had gas exchange abnormalities sufficient to warrant extracorporeal membrane oxygenation. The incidence of bronchial complications requiring intervention, median duration of posttransplantation mechanical ventilation, length of stay in the intensive care unit, and hospital length of stay were also similar.

Two of 20 patients in the EVLP group died within 30 days (10%) compared with 6 of 116 control patients (5.3%; P = .33). No serious adverse events were attributed to EVLP, he said.

The survival rate at 1 year was 80% in the EVLP group and 83.6% in the control group (P = .54). At a median follow-up of 561 and 542 days, respectively, 15 (75%) of the 20 recipients of EVLP lungs and 94 (81%) of 116 control patients were alive.

Updated Outcomes

In an update to the published results, Dr. Cypel reported on 43 patients who have undergone EVLP, of whom 35 (81%) were transplanted and 8 (19%) were rejected after 4 hours of EVLP. Of the 35 transplanted patients, 23 have been followed-up for 1 year. Their 1-year outcomes were compared with those of the 116 control patients.

One-year survival was 83% for the EVLP group and 83.6% for the control group. Survival rates at 1, 3, and 6 months were also not significantly different. Median follow-up is now 635 days, and no differences have emerged, he said.

Lung function remained preserved in the EVLP group, and there was no difference in the occurrence of chronic lung allograft dysfunction at 1 year. Bronchiolitis obliterans syndrome rates at 1 year were 10.5% in the EVLP group and 9.5% among control patients. Bronchial complication rates were also low — approximately 4% in each group.

Plenary session moderator and program chair for the meeting Richard Pierson, MD, from the University of Maryland in Baltimore, commented that the findings represent "clinical application of an idea we have worked on for a decade."

"Extracorporeal resuscitation of lungs is likely to be useful for expanding access to donor lungs. The future, I think, is that the device can be used to treat the lungs with medications to reverse the causes of lung dysfunction, and perhaps to treat infections that currently prevent us from using some donor lungs," he said. "In principle, EVLP could also be used to administer gene therapy or other treatments to improve long-term outcomes after transplant. It's exciting to see this turning into something we can use for patient care."

Dr. Cypel and Dr. Pierson have disclosed no relevant financial relationships. Dr. Cypel noted that although the study was sponsored by Vitrolife, the company was not involved in the conduct of the study, analysis or storage of data, or the preparation of the manuscript.

International Society for Heart and Lung Transplantation (ISHLT) 31st Annual Meeting and Scientific Sessions: Abstract 1. Presented April 14, 2011.

N Engl J Med. 2011;364:1431-1440. Full text

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