NEW YORK (Reuters Health) – Normothermic machine perfusion may be superior to conventional static cold storage for preserving livers and other organs for transplantation, two new randomized trials suggest.
“Preserving livers under physiological conditions not only improves outcomes after liver transplantation, but also enables more organs to be transplanted without increasing the risks to the patient,” Dr. David Nasralla of the University of Oxford, U.K., who worked on one of the studies, told Reuters Health by email.
Conventional preservation, which involves flushing the liver with special preservation fluid, cooling, and storing it in an icebox, can be associated with severe ischemia-reperfusion-related morbidity. To avoid this, normothermic machine perfusion (NMP) was developed to perfuse the liver with oxygenated blood, medications and nutrients at normal body temperature to maintain a more physiological environment.
Dr. Nasralla and colleagues in the Consortium for Organ Reservation in Europe investigated the efficacy of NMP versus conventional cold storage in a randomized controlled trial in which 220 livers were available for primary-outcome reporting.
The organ-discard rate was significantly lower in the NMP arm (16/137, 11.7%) than in the static cold storage (SCS) arm (32/133, 24.1%). Post-reperfusion syndrome was also significantly less common in the NMP group (15/121) than in the SCS group (32/97), the researchers report in Nature, online April 18.
Peak levels of serum aspartate transaminase (AST) within seven days after transplant, the primary endpoint, were 49.4% lower in the NMP group than in the SCS group, with significant reductions seen for donors declared dead by cardiovascular criteria (DCD) as well as brainstem-death donors (DBD).
Early allograft dysfunction developed in fewer NMP livers (12/119) than SCS livers (29/97), an odds reduction of 72% after adjustment for donor type and other factors.
There were no differences between the groups in the rates of biliary strictures, intensive care unit and hospital stay durations, need for renal replacement therapy in the first postoperative week, graft survival or mortality at one year.
“There is no doubt that the liver-transplant surgeons who have experienced the NMP technology are its strongest advocates,” Dr. Nasralla said. “Nonetheless, the current challenge is to translate these exciting results into a change in routine clinical practice. Two further pieces of emerging evidence will facilitate this.”
“First,” he said, “additional data are needed to test whether NMP enables livers to be transplanted that are outside current criteria: a trial is being conducted at the University of Birmingham to address this specifically.”
“Second, evidence is needed to assess the cost-effectiveness of this technology: NMP is not necessarily expensive when taken in the context of the cost of keeping patients alive whilst waiting for a liver,” Dr. Nasralla said. “Reducing the number of discarded organs will increase the number of transplants and reduce waiting list morbidity and cost. There are major logistic and cost advantages of prolonged preservation (e.g., daytime operating). In addition, a smoother postoperative course may further offset the cost of NMP compared to icebox storage.”
Dr. James F. Markmann, chief of transplant surgery at Massachusetts General Hospital in Boston, told Reuters Health by email, “This large randomized trial provides the best evidence to date that this novel technology has the power to make more livers available for transplantation. This will save countless lives of patients awaiting transplant. It appears inevitable that this technology will rapidly permeate the field and become the standard preservation approach.”
“It will be important to repeat these studies in the U.S. where the patients are typically more critically ill than the cohort transplanted in this trial,” he said. “It will be important to demonstrate that the transplant teams will be able to manage the pumps independent of study team experts.”
“There are a couple noteworthy problems with the study,” Dr. Markmann added. “Perfect organs, such as those from young donors with short ischemia that would not be expected to derive benefit from normothermic perfusion were included in the study; this likely lessened the benefit observed. The pump was allowed to be used in a non-rigorous manner, resulting in many cases of prolonged perfusion, presumably for surgeon convenience, that may have lessened the observed benefit of the approach.”
The study did not have commercial funding. Two of Dr. Nasralla’s coauthors report ties to OrganOx Ltd., which made the normothermic device used in the study.
In the second trial, online April 9 in The Lancet Respiratory Medicine, Dr. Gregor Warnecke from Hannover Medical School in Germany and colleagues tested the use of normothermic ex-vivo lung preservation (EVLP) with a portable device for bilateral lung transplantation (Organ Care System, TransMedics Inc).
The primary effectiveness composite endpoint was patient survival at day 30 and the absence of grade 3 primary graft dysfunction (PGD3) within the first 72 hours post-lung transplantation. This was found to be noninferior with normothermic preservation (112/141, 79.4%) versus conventional cold storage (116/165, 70.3%).
The individual components were significantly different between the normothermic group and the conventional group, with better 30-day survival in the conventional group (100% vs. 95.7% in the per-protocol population) and less PGD3 in the normothermic group (17.7% vs. 29.7%).
Dr. Warnecke told Reuters Health by email, “I think the most important message is that we actually can reduce the rate of severe primary graft dysfunction (PGD3) by applying this new technology. In this finding, there is the prospect of improved early outcomes and consecutively reduced late chronic rejection (CLAD, chronic lung allograft dysfunction). This would be because CLAD is known to be associated with PGD3 in the first 72 hrs. While we yet have to prove the long-term benefit, the prospect appears real, and there are few things that fascinate lung-transplant professionals more than reducing PGD and CLAD.”
“While we can safely use the device in all-comers, additional work in future will help us to dissect out the type of lung donors and recipients that benefit most from portable EVLP with the OCS (Organ Care System),” he said. “We already designed a prospective registry to collect data on future lung transplants using the OCS to help with these analyses in future.”
Dr. Allan R. Glanville from St. Vincent’s Hospital in Darlinghurst, Australia, who wrote an editorial related to this report, told Reuters Health by email, “A robust cost-utility study should be performed to assist health care providers to make efficient use of this precious resource, donor tissue, which may be life-saving, life-prolonging, and lead to improvements in quality of life.”
“Portability of the OCS device is a key area of benefit when considered alongside other devices,” he said.
TransMedics Inc. funded the trial and had financial relationships with several authors, including Dr. Warnecke.
SOURCE: https://bit.ly/2EXkRg2 https://bit.ly/2HKoEAb and https://bit.ly/2H8vNNE
Nature 2018.
Lancet Respir Med 2018.
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