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Received: 29 January 2018 Revised: 15 April 2018 Accepted: 15 May 2018 DOI: 10.1111/ajt.14945
SPECIAL ARTICLE
Implementing an innovated preservation technology: The American Society of Transplant Surgeons’ (ASTS) Standards Committee White Paper on Ex Situ Liver Machine Perfusion Cristiano Quintini1 | Paulo N. Martins2 | Shimul Shah3 | Mary Killackey4 | Alan Reed5 | James Guarrera6 | David A. Axelrod7 | for the American Society of Transplant Surgeons Standards Committee 1
Cleveland Clinic Foundation, Cleveland, OH, USA
University of Massachusetts, Worchester, MA, USA
2
3
University of Cincinnati, Cincinnati, OH, USA
Tulane University School of Medicine, New Orleans, LA, USA
The pervasive shortage of deceased donor liver allografts contributes to significant waitlist mortality despite efforts to increase organ donation. Ex vivo liver perfusion appears to enhance preservation of donor organs, extending viability and potentially evaluating function in organs previously considered too high risk for transplant.
4
5
University of Iowa, Iowa City, IA, USA
Rutgers University School of Medicine, Newark, NJ, USA
6
Lahey Hospital and Medical Center, Burlington, MA, USA
These devices pose novel challenges for organ allocation, safety, training, and finances. This white paper describes the American Society of Transplant Surgeons’ belief that organ preservation technology is a vital advance, but its use should not change fundamental aspects of organ allocation. Additional data elements need to be
7
collected, made available for organ assessment by transplant professionals to allow determination of organ suitability in the case of reallocation and incorporated into
Correspondence David A. Axelrod Email:
[email protected]
risk adjustment methodology. Finally, further work is needed to determine the optimal strategy for management and oversight of perfused organs prior to transplantation. KEYWORDS
clinical research/practice, editorial/personal viewpoint, liver transplantation/hepatology, organ perfusion and preservation, organ procurement, organ procurement and allocation, organ procurement organization, risk assessment/risk stratification
1 | I NTRO D U C TI O N
the potential consequences (unintended or potentially foreseen) generated by such technology. This white paper stemmed from a
In the past 5 years, the field of extrarenal machine preservation
discussion convened at the American Transplant Congress in 2017
has witnessed remarkable advancements. Once experimental,
of leaders in the field of liver perfusion. The statement was au-
machine liver perfusion is now being tested in large clinical trials
thored by members of the Scientific and Standard Committee of
worldwide. As with any novel technology, it is important that the
the American Society of Transplant Surgeons (ASTS) and leaders
transplant field recognizes and prepares for the challenges and
in the field of organ perfusion. The authors solicited additional review by multiple experts and endorsement from the ASTS
Abbreviations: CIT, cold ischemia time; DCD, donation after cardiac death; EAD, early allograft dysfunction; HMP, hypothermic nonactively oxygenated perfusion; HOPE, hypothermic machine perfusion using oxygenated perfusate; LDLT, living donor liver transplant; NMP, normothermic machine perfusion; OPO, organ procurement organization; SAC, standard acquisition cost; SCS, static cold storage.
Am J Transplant. 2018;1–10.
Council. The manuscript outlines potential emerging regulatory, scientific, logistical, and financial challenges related to the implementation of machine organ preservation of liver allografts in clinical practice. Furthermore, it highlights the obstacles that
amjtransplant.com
© 2018 The American Society of Transplantation | 1 and the American Society of Transplant Surgeons
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must be overcome to successfully transition from sponsored clin-
of human liver perfusion devices did not move forward for liver trans-
ical trials to a possible new standard of care.
plant.9 However, hypothermic machine perfusion in kidney transplant has been a mainstay of transplant practice, prolonging organ viability and reducing delayed graft function.10-13 Moers and col-
2 | TH E PRO B LE M
leagues’ 2009 New England Journal of Medicine paper demonstrating
Liver transplantation continues to be plagued by the gap between organ demand and supply. Options to increase the donor pool including donation after cardiac death (DCD), living donor liver transplant (LDLT), and split liver transplant are limited by current outcomes and donor availability. Mortality on the waiting list has steadily in1,2
creased since 2009.
Although efforts to expand the organ supply
should continue, optimizing grafts that are currently discarded provides the best opportunity to decrease the mortality on the waiting list. Effective strategies to maintain or enhance organ function are equally important, as the overall quality of available allografts 2
is declining. In addition, proposals to encourage broader sharing of liver allografts in the United States are likely to result in prolonged ischemic times, further compromising outcomes in at-risk organs.3,4 The current organ preservation technology, static cold storage (SCS), remains a significant barrier to the broader use of “marginal grafts.” Liver grafts with risk factors for poor allograft function including advanced donor age, macrosteatosis, and DCD recovery, seem to be particularly susceptible to the effects of prolonged cold ischemia and the direct cell injury that occurs during SCS.
5-8
Furthermore, static
preservation at cold temperatures precludes organ functional assessment and organ intervention, both of which require metabolically active cells. Therefore, the ideal preservation technology should provide:
improved 1-year graft survival of human kidney grafts with machine preservation regenerated interest in broader application of perfusion techniques for extrarenal transplantation. Ex vivo perfusion was also demonstrated to be effective in thoracic transplantation by pioneers including Shaf Keshavjee (lung) and Waleed Hassanein (heart) 14-16 In 2010, successful clinical application of nonactively oxygenated, hypothermic liver machine preservation was reported by Guarrera et al. Subsequent successful clinical trials were conducted in continental Europe, Canada, and the United Kingdom.17-25 These investigators demonstrated the promise of preservation technology by successfully transplanting allografts that were declined by all centers and would have been discarded.19,23 In 2018, the use of pulsatile perfusion was extended to allow ischemia-free transplantation in humans. Dr. He and colleagues reported continuous perfusion of a steatotic deceased graft from recovery through transplantation. 26 Although rapidly gaining acceptance and interest, machine liver preservation is still in its infancy. 27 Many important features are still being evaluated and tested. For instance, the ideal perfusion solution, temperature, rewarming time, and perfusion protocols (medication and supplements to infuse) remain unknown. It is also not clear whether device portability has a marked impact on allograft function. At the present time three main types of devices are being evaluated in clinical trials in the United States and abroad: hypothermic
1. A preservation environment able to maintain cell viability for
machine perfusion using oxygenated perfusate (HOPE), hypother-
a prolonged time and halt preservation injury even in the
mic nonactively oxygenated perfusion (HMP), and normothermic
most severely damaged grafts
machine perfusion (NMP)5,6,28,29 (Table 1).
2. An organ assessment platform capable of predicting posttransplant function 3. An opportunity to evaluate and recondition initially untransplantable grafts
Hypothermic machine perfusion (HMP) devices operate between 4°C and 10°C and use acellular preservation solution similar to those used in SCS. The HMP assists with recovery of mitochondrial function, reconstitution of ATP levels, and elimination of cat-
4. Economic efficiency sufficient to encourage widespread use
abolic by-products from the endothelial space.30,31 Based on their
5. The potential to be transportable to allow broader sharing of re-
pioneering work, the Columbia group has concluded that HMP is safe
covered and perfused grafts within our current policy (or reason-
and feasible and holds the potential to successfully rescue nontrans-
able policy revisions)
plantable grafts.18,32 Currently, 44 livers have been preserved and
6. A reliable perfusion platform with a safe and dependable backup plan in the case of device failure
transplanted using this technology. The Organ Recovery Systems trial, which is about to start accruing patients in the United States, uses Vasosol® as the perfusate to promote vasodilation, reduction
The ideal technology would translate into an increase in the num-
of oxidative stress and mitochondrial injuries, and opening of the mi-
ber of transplants, reduction of liver discard rates, and a decline in
crovasculature.33,34 Assessment of organ function with HMP may
waitlist mortality, providing it is not cost prohibitive for transplant pro-
be possible as perfusate aspartate aminotransferase (AST) has been
grams. Ex situ machine preservation holds the potential to satisfy these
shown to have a statistically significant correlation with peak recipi-
requirements.
ent AST, an accepted marker of ischemia/reperfusion (preservation)
3 | CU R R E NT S TATE O F E X S IT U M AC H I N E PR E S E RVATI O N
injury.34 Current trials of HMP are designed to demonstrate safety and noninferiority when compared to SCS and, it is hoped, to advance adoption of machine perfusion. Dutkowski and colleagues have reported the use of dual hypother-
After the early unsuccessful attempts at hypothermic perfusion of
mic oxygenated machine perfusion (DHOPE) in Europe for DCD livers.
human livers by Starzl et al in 1967, the clinical use and development
Unlike HMP, DHOPE uses actively oxygenated hypothermic perfusion
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TA B L E 1 Table of mechanical perfusion devices in clinical trial in the United States Name company/entity Columbia University (Guarrera team)
Normothermic/hypothermic
Date trial started
Perfusate
Hypothermic
2004 July
Hypothermic
2009 Dec
Vasosol solution (based on Belzer- MPS)
TransMedics (OCS) Liver Trial: Preserving and Assessing Donor Livers for Transplantation (Liver PROTECT)- NCT02522871
Normothermic
January 2016
Packed Red Blood Cells (PRBCs) + Gelofusine
Normothermic Liver Preservation. NCT02775162 OrganOx Ltd.
Normothermic
June 2016
PRBCs + albumin
Pilot Study to Assess Safety and Feasibility of Normothermic Machine Preservation In Human Liver Transplantation. NCT02775162 Cleveland Clinic. Cleveland, OH, USA
Normothermic
May 2016
PRBCs + Fresh frozen plasma
of allografts via the portal vein for 1-2 hours following a period of SCS.
Normothermic machine preservation was pioneered by Friend
Results from 2 European studies on DCD livers demonstrated reduced
and colleagues in England, Selzer and colleagues in Canada, and
peak ALT, cholangiopathy, and biliary complications compared to SCS.
Hassanein in the United States. 23,41 Unlike hypothermic devices,
One-year graft survival was also improved and the need for retrans-
normothermic perfusion has generally been initiated as soon as
plantation reduced by DHOPE- treated livers when compared with
possible after organ recovery. The first liver transplant performed
SCS- treated DCD grafts (18% SCS to 0% DHOPE). The DHOPE trial is
in the world using NMP occurred in 2013.41 In Toronto, Selzner and
currently enrolling patients in multiple European centers.17,35
colleagues performed the first North American clinical trial using
The hypothermic machine perfusion trial (HOPE) trial is a phase
NMP. 24 Initial results suggest that NMP is safe, feasible, and associ-
2 trial conducted in Europe by Drs. Dutkowski and Clavien that ran-
ated with excellent graft preservation, despite the marked increased
domizes patients to HOPE perfusion vs standard preservation for
in the complexity of these devices. Furthermore, NMP offers the
patients transplanted with livers recovered from brain-dead donors.
opportunity to directly assess graft function during preservation.
The organs are perfused for 1 hour after preparation of the allograft.
There are now several reports suggesting that NMP can be used
The primary outcome is the rate of postoperative complications,
to evaluate grafts initially thought unusable, thereby expanding the
whereas secondary outcomes include physiologic, laboratory, and
organ supply.42-45 This perfusion can be applied at the time of recov-
long-term outcomes.36 Additional endpoints including resource uti-
ery or after a period of SCS while standard allocation protocols are
lization and organ pathology will also be assessed. A second study
exhausted. Watson et al report the end ischemic NMP of 47 grafts
(HOPE ECD- DBD) is being led by Czigany et al in Aachen, Germany.
and subsequent transplant of 22 livers based on assessment of graft
Similar in design to the HOPE trials, the HOPE ECD- DBD will ran-
function. 20 Although viability markers have yet to be definitively es-
domize patients receiving ECD livers, which were defined as age > 65,
tablished, the following seem very promising: bile (amount produced,
ICU treatment > 7 days, donor body mass index (BMI) > 30, > 40%
pH, bicarbonate levels, glucose level), perfusate (lactate clearance,
macrosteatosis, serum sodium > 165 mmol/L, AST or ALT > 3 times
glucose metabolism, enzyme release, pH trend), and hemodynamic
normal, or a serum bilirubin > 2 mg/dL.37 Organs randomized to the
parameters (PV/HAP flows, pressure, and flow resistance). 20
HOPE ECD- DBD protocol will receive 1- 2 hours of hypothermic por-
Information obtained from the ClinicalTrials.gov website indi-
tal perfusion and will be compared with SCS in HTK solution. The
cates that there are currently 4 ongoing machine perfusion trials in
primary endpoint of the trial is peak transaminase levels. Secondary
the United States (Table 1), 3 of which utilize a normothermic device
endpoints are similar to the HOPE trial.
(Organox®, Transmedics®, and the Cleveland Clinic Device) and 1
Several aspects of HMP remain to be worked out. First, HMP ma-
with a hypothermic device (Organ Recovery Systems, Chicago, IL).
chine perfusion has been utilized for several hours at the transplanting
If successful, these technologies may be commercially available to
center after a period of SCS (end-ischemic). There are no trials compar-
transplant centers by 2020. The primary endpoint of these trials is
ing early HMP with delayed perfusion. Second, beneficial results were
the reduction of posttransplant early allograft dysfunction rate (EAD)
obtained with single perfusion (portal vein alone: HOPE and DHOPE
defined as the presence of one or more of the following: bilirubin
trials) as well as dual cannulation (hepatic artery and portal vein:
> 10 mg/dL on day 7, international normalized ratio > 1.6 on day 7
Columbia group), without clear superiority of one technique.31,38-40
and alanine or aspartate aminotransferases > 2000 IU/L within the
Third, there is no consensus whether active oxygenation (HOPE,
first 7 days.46 Although not ideal, EAD occurs frequently enough to
DHOPE) or nonactive oxygenation (Columbia/Organ Recovery
make reasonable comparisons of device efficacy as compared to SCS.
Systems) of perfusate is needed for hypothermic perfusion. These and
Although the incidence of ischemic cholangiopathy is crucial to mea-
other issues need clarification through the ongoing clinical trials.
sure in DCD transplant, it is more difficult to clearly define and its
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delayed occurrence would extend trials. In consensus meetings, many
30% of kidneys are pumped. In liver machine perfusion, there will
liver transplant leaders also suggest that some appropriate measure
be an adjustment phase when transplant surgeons and programs
of “organ utilization” should be considered as a relevant endpoint, but
become familiar with the technology and its indications after ap-
this is not a feasible primary endpoint for safety studies or first com-
proval. It is expected that at the beginning there will be a selec-
parison trials.
tive use of the technology on higher risk donors. However, we
Current US machine trials of NMP are designed to prove nonin-
hypothesize there may be broader use in standard criteria donors
feriority of machine perfusion over SCS when employed in organs
to allow prolonged cold ischemic times, improve organ assess-
deemed initially transplantable by the accepting centers. Therefore,
ment, and reduce logistical complexity.
the devices are not being used in the United States to assess and/or rescue organs. This is important because randomization to machine perfusion or SCS occurs after allocation to a primary recipient. A potential concern with this design is the process of reallocating a “re-
4.1.1 | Who should decide which organs should be pumped, the transplanting center or the OPO?
search” organ when the intended recipient is no longer a candidate
We believe that standard criteria for liver perfusion should be es-
for transplant. At this point the liver already been placed on the device
tablished by the liver transplant community as it is commonly done
may be offered/transplanted into a patient who is not enrolled in the
in kidney transplants once the trials have been completed and clear
clinical trial in a nonparticipating center (ie, allocated in accordance
data are available. For example, allografts at highest risk of primary
with UNOS policy). It is our opinion that the organ should be allocated,
nonfunction or early allograft dysfunction should be perfused (eg,
according to the standard organ allocation rules, to the next recipient
DCD, steatosis, older age, anticipated long cold ischemic time,
on the match run list (not the next patient consented in the trial). The
hemodynamically unstable donor). In addition, organs that are de-
recipient would have to provide consent to receive an organ that is
clined by all regional centers can be considered for perfusion to
being preserved using an experimental technology prior to receiving
allow resuscitation and assessment and time for further placement
the transplant. In addition, if the organ is not utilized in the intended
efforts. Given the high cost and potential risk of these devices, use
recipient, the center or local organ procurement organization (OPO)
of perfusion to improve operational logistics alone should be dis-
will be required to repackage the allograft in SCS to be sent to the ac-
couraged. Clearly, centers should have the ability to request pump-
cepting center. We do not support the reallocation of the organ only
ing in additional circumstances when clinically indicated especially
to recipients who have been enrolled in the trial for machine preser-
if the perfusion will be performed at the accepting center.
vation as this unfairly affects patients listed at centers that are not
With broader application of machine perfusion, there will be in-
enrolled in a specific clinical trial. It is anticipated that this would be an
stances in which the accepting program places the organ on the per-
infrequent event as the recovering center should have evaluated the
fusion device and then declines it after on-pump assessment as has
allograft at recovery and formally accepted the liver prior to initiating
been done with other organs. These organs must then be offered
perfusion. Centers enrolled in trials should proactively address the
to other centers for their consideration. The transplant community
issue of reallocation with other centers in their donation service area
must track the outcome of all organs perfused to make sure that
and region to ensure that they develop sharing protocols and comply
the use of the pump does not increase discard rates of otherwise
with all Organ Procurement and Transplantation Network (OPTN) re-
transplantable allografts (unintended consequences). The ASTS fa-
quired packaging and labeling protocols.
vors monitoring of allograft acceptance and decline rates among perfused organs to identify practices that lead to excessive organ discard. 14,47,48 It is the opinion of the ASTS that proactive quality as-
4 | LO G I S TI C A L I S S U E S I N E X S IT U M AC H I N E PR E S E RVATI O N I M PLE M E NTATI O N
surance processes and data-driven initiatives will be key to mitigate the challenges related to the implementation of such an innovative practice. Careful monitoring of real-time data, as is currently occurring in the Collaborative Innovation and Improvement Network proj-
Assuming regulatory approval of the currently tested ex situ preser-
ect conducted by the United Network for Organ Sharing (UNOS) to
vation devices is obtained, there are important clinical, logistical, and
improve kidney utilization, will be helpful to assess benefit and risk
financial ramifications that need to be considered.
of this new technology.
4.1 | Organ selection
4.2 | Organ perfusion
It is not clear how frequently machine perfusion technology will
As noted, organ perfusion is a complex undertaking requiring sur-
be used in liver transplantation. In kidney transplant, the use of
gical expertise and careful monitoring. Although kidney perfusion
perfusion is restricted to organs that are most likely to have de-
is largely handled by the OPOs, it is likely the liver perfusion will
layed graft function or primary nonfunction given the high cost
require direct transplant center involvement from the time of organ
of the device and disposable components. Currently, less than
recovery to transplantation.
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4.2.1 | Who should be responsible for the initial perfusion and evaluation of the graft, the OPO or the transplant center?
4.2.4 | Where should perfusion be initiated and is there a benefit to immediate perfusion that requires portable devices?
We believe that each OPO and its associated liver transplant cent-
There are currently no conclusive clinical data establishing the safety
ers should develop a consensus-based approach to this issue. As
or superiority of immediate machine perfusion that requires a porta-
outlined next, there are significant economic and logistical benefits
ble device compared to initial SCS and subsequent perfusion. Recent
to transplant programs if the OPOs assume responsibility for perfu-
clinical trials have demonstrated that the organ can initially undergo
sion as is currently done in kidney transplant. However, this will re-
cold static preservation for transportation with subsequent perfu-
quire significant investments in OPO staff training and resources. In
sion after arrival at a central location or transplant center without
addition, warm perfusion prior to organ acceptance may be a source
harm.17 This finding is important as not all current devices are easily
of concern for transplant programs unless quality of the perfusion is
transportable. An alternative to center-based perfusion is the estab-
carefully monitored and assessed.
lishment of a regional perfusion center to cannulate, pump, monitor, and distribute organs following recovery. This type of center would
4.2.2 | Who will be responsible for cannulation, transportation and monitoring of the organ prior to transplant?
also allow for expedited recovery prior to organ allocation. It is likely
We believe that, in general, the accepting surgical team should be
could reduce potential conflict between centers that have the re-
responsible for placement of the organ on the device and initial mon-
sources to purchase, utilize, and monitor the device and others that
itoring, as they will subsequently be transplanting the organ. For or-
would consider these organs for transplant but lack the resources to
gans that are not allocated prior to recovery, the recovering surgeon
establish a program of their own. Additional study is also needed to
could place the organ in SCS for transportation to the final accepting
determine the benefit of early perfusion at the site of organ recov-
center with subsequent perfusion.
ery vs delayed perfusion, particularly in higher risk donors including
that the centers would expect the organ to be delivered on the perfusion device to prevent the need for a second prolonged period of cold storage. The establishment of centralized perfusion centers
DCD recovery or significant steatosis.
4.2.3 | How long should accepting centers be allowed to perfuse the organ prior to acceptance/ decline of the organ?
4.2.5 | Where should perfusion take place? Maintenance and assurance of sterile technique will be crucial to
Although the maximum period of safe perfusion is still unknown,
prevent infections particularly when the organ is perfused at nor-
the transplant community should start working on guidelines to
mothermic temperature. NMP, at least theoretically, increases the
ensure that efficiency in allocation and reallocation is not impeded
chance of microbial growth prior to transplantation. Therefore, can-
by machine perfusion. Research protocols using discarded human
nulation and perfusion must be performed in a location that meets
liver allografts have demonstrated that NMP can reliably perfuse
current standards for performing sterile (aseptic) clinical procedures
livers for periods of up to 24 hours; however, efficient allocation
either at the OPO or at the transplant center. Centers will need to
mandates that perfusion should be limited to much shorter
establish either a specialized perfusion room or utilize an operating
periods. 49 Specifically, centers need to make timely decisions to
room to ensure all appropriate tissue handling protocols are main-
allow reallocation of the organ to other centers based on cur-
tained. It is important that organ perfusion not be considered as tis-
rent allocation policy. Although clearly longer than the 1 hour
sue manipulation, however, as this requires additional regulation (as
allowed with SCS, the transplant community needs to determine
is currently in place for islet preparation).
a maximal time to decision for a perfused organ. We believe that centers should be limited to 4- 6 hours of perfusion prior to acceptance or decline of the organ to allow timely reallocation of
5 | G R A F T A S S E S S M E NT A N D SA FE T Y
the organ. This period was chosen as this is less than the median pumping time in early clinical trials, allows ample time to real-
One key goal of machine preservation is to increase the organ ac-
locate the organ should the initial center decline the organ, and
ceptance rate, particularly for marginal organs that are currently
provides a meaningful period to assess liver function. We also
discarded. In 2015, 2000 organs were procured and discarded after
need to be sure that we do not increase the risk of adverse out-
procurement.50 In the future, some of these organs will be perfused,
comes including primary nonfunction, organ discard from me-
resuscitated, and reevaluated. Therefore, the perfusing center or
chanical failure, or repeated allocation out of sequence events
OPO will need to ensure the safety of the organ perfusion pro-
due to late decisions.
cess and then provide an assessment of the donor organs to allow
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Basic data
• Type of perfusate used • Device employed o Type of cannulation • Time of initial perfusion • Portable vs stationary (“back to base”) perfusion • Duration of CIT, device perfusion time, and total preservation time • Amount of SCS time prior to perfusion
Organ assessment
• Perfusion temperature – hourly • Hemodynamic parameters o HA/PV flow rate to be recorded – hourly • Bile production – cc per hour for NMP • Laboratory values time 0 and hourly o Bile glucose o Blood glucose o Biliary bicarb and pH levels o pH and lactate levels • Macroscopic assessment • End of perfusion biopsy
Pharmaceutical treatments administered
• Antibiotics • TPN solution • Other adjunctive treatments
Safety
• Blood culture at the beginning and at the end of preservation • Personnel
TA B L E 2 Required data submission for perfused organs
CIT, cold ischemic time; SCS, static cold storage; HA/PV, hepatic artery/portal vein; NMP, normothermic machine perfusion; TPN, total parenteral nutrition.
accurate clinical decision making. 21,44,45,51-54 This is particularly im-
center and OPO will need to establish training protocols and proce-
portant for reallocated organs in which the initial center declines the
dures that adhere to accepted guidelines as defined by the OPTN,
organ after perfusion.
Health Resources and Services Administration (HRSA), and the Food and Drug Administration (FDA). This training must include an un-
5.1 | Which data elements should be recorded and at what interval?
derstanding of the parameters that necessitate involvement of a
“On pump” viability markers must be documented and shared with
tect deteriorating allograft function, and have the ability to safely
surgeon. The perfusion professional should be able to identify and remedy device malfunction, administer appropriate medications, de-
the OPO and other centers. 20 Based on the literature and current
convert machine preservation to static cold storage in case of unre-
knowledge we recommend that the data elements summarized in
coverable device failure within 10 minutes of cessation of perfusion.
Table 2 be routinely collected and available through UNet in order to allow accurate assessment of donor quality and permit retrospective review of all posttransplant graft and patient deaths.
5.2 | What training standards should organ transplantation personnel be required to meet?
5.3 | What role should the OPOs have to ensure transparency, organ safety, and quality assurance/ process improvement? Transplant programs and the OPOs share responsibility for ensuring organ safety. Clearly this is more complex in the setting of machine
SCS does not require any specific graft monitoring during pres-
perfusion, which prolongs organ preservation and provides an op-
ervation, although strict packaging, labeling, and tracking are re-
portunity for organ damage after recovery and prior to transplanta-
quired. The introduction of ex situ machine preservation introduces
tion. This differs from SCS in which the organ is generally packed and
the need for continuous graft monitoring during preservation.
not manipulated. However, this shared responsibility is not unprec-
Accidental decannulation, vessel kinking, interruption of oxygen,
edented. Currently, organs are reallocated following organ prepara-
power supply, or perfusion outside of the target hemodynamic and
tion in the case of a recipient death or finding of unsuitability. In this
manufacturer-recommended parameters are just some examples of
situation, the transplant center or cooperating OPO is responsible
potential device malfunctions that may result in irreversible organ
for repackaging the organ for transportation to an accepting center.
injury during normothermic preservation.
In the case of machine perfusion, we believe that the transplant
Specially trained personnel must be able to operate the device
center and OPO community need to work together to develop pro-
throughout preservation and be immediately available to intervene
tocols to ensure that the organ is safely transplanted. In the case
should a malfunction occur, especially with NMP as failure to do
of SCS, the OPO is responsible for the organ until it is delivered
so would lead to unacceptable pretransplant warm ischemia. Each
to the center and removed from sterile packing. If the transplant
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program performs the perfusion, it assumes responsibility for es-
of DonorNet data could be directly entered into UNet. In addition,
tablishing procedures that ensure the safety of the donated organ.
more granular, center-specific data collected under clinical trials
This exposes the transplant center to potential liability should the
would need to be gathered, monitored, and shared as a scanned
organ be contaminated or injured prior to reallocation to a different
document in the case of reallocation.
transplant program Alternatively, if the OPO is performing the perfusion, the OPO retains responsibility for organ quality and safety until the organ is removed from the perfusion device for final graft preparation.
7 | R EG U L ATI O N A N D I NTE R AC TI O N W ITH TH E FDA , H R SA , A N D O P TN Interaction of transplant professionals with regulatory bodies will be
6 | DATA CO LLEC TI O N
crucial in successful development and implementation of machine preservation. The ASTS strongly endorses the position that machine
As for any new technology, it is important to prospectively collect
perfusion, as currently performed, is not manipulation of tissue, but
data that can be used to assess organ viability and provide informa-
rather an improved preservation technology. It is anticipated that
tion to the Scientific Registry of Transplant Recipients (SRTR) and
the perfusion device will be approved by the FDA, but the process
other regulatory bodies. There are unique challenges of machine
of organ recovery, preservation, assessment, and transplant will be
perfusion, particularly NMP. One example might be the definition of
monitored by HRSA and the OPTN. In the future, it may be pos-
cold ischemic time (CIT). CIT is currently used to adjust risks of trans-
sible to provide adjunctive treatments to address donor steatosis
plant outcomes and is defined as time of cross-clamp in the donor
or otherwise alter the donor organs. Should these techniques be
to initiation of organ implantation. Because CIT will be altered by
developed and introduced, additional conversations with federal
NMP, a new definition of preservation time will have to be included
regulatory agencies will be needed to determine the primary locus
in UNOS/SRTR reporting. It is unclear what effect this will have on
of regulation.
outcome, potentially rendering the risk adjustment models less useful. We suggest that the following times be recorded for all perfused allografts: cross-clamp time, time of removal from the donor and placement in SCS, time perfusion is initiated, time perfusion is com-
8 | FI N A N C I A L I M PLI C ATI O N S O F M AC H I N E PE R FU S I O N
pleted, any interruption in perfusion and length of time, and time of reperfusion. Organs managed with NMP and HMP will require new
It is anticipated that machine perfusion could add $25 000-50 000
definitions of cold ischemic time (cross-clamp to initiation of perfu-
to the cost of a single liver transplant, given the cost of the device,
sion), warm ischemic time (cessation of perfusion to reperfusion in
disposables, personnel, blood products, increased donor OR time,
the recipient), and total preservation time (cross-clamp to reperfu-
pharmaceutical agents, and other costs not incurred with SCS. The
sion in the recipient).
allocation of this cost to affected transplant programs has the potential to create significant economic disincentives to broader use
6.1 | What data should be included in risk adjustment?
of this lifesaving technology. Current reimbursement for transplant
Risk adjustment is designed to assess the impact of nonmodifi-
3 separate payments for technical services via a diagnosis-related
able risk factors that affect the outcome of transplantation.
group (DRG) payment under Part A, physician/surgeon payment via
Conversely, the impact of center practice decisions is not “ad-
Part B, and reimbursement for organ acquisition and other pretrans-
procedures involves payment for clinical care (professional and technical services) and payment for organ acquisition. Medicare provides
justed” for by the equations. Because organ preservation may or
plant costs via the hospital cost report. However, many private pay-
may not be a center decision initially, we believe that the SRTR
ers reimburse using a single case rate that encompasses the full cost
should consider machine perfusion in the risk equations. At a min-
of the procedure.
imum, the SRTR should incorporate the type of perfusion: SCS,
In the case of the machine perfusion, the impact of the cost de-
hypothermic perfusion, or normothermic perfusion. In addition,
pends upon which entity is performing the perfusion. If the OPO
data on total perfusion time should be included. It is expected
performs the perfusion, the cost of the device and disposables can
that, like kidney transplantation, perfusion will actually reduce
be incorporated into the total cost of all livers recovered for the year
the risk of organ failure over time; however, this will require fur-
and distributed to all centers served by the OPO. Therefore, the
ther study.
cost of machine perfusion will be shared by all transplant centers,
Data collection should not represent an unnecessary burden
increasing the standard acquisition cost (SAC) billed to centers for
to transplant centers. Although much of this data should be elec-
a liver allograft. This will reduce the per case cost of MP but will
tronically captured by the device, some additional data submission
increase the SAC costs for all centers. Because all centers benefit
will be required. A stepwise approach may be most beneficial to the
from an expanded donor pool, it may be rational that they share
transplant community. In the early phase of device approval, a core
in the cost of the procedure. This cost allocation is similar to renal
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transplant perfusion in which all centers share the cost of organ per-
QUINTINI eT al.
9 | S U M M A RY
fusion. Alternatively, the OPO can assess a surcharge for mechanical preservation to centers that utilize it. An OPO- based cost structure
Although ex situ machine liver preservation is not yet an approved
may assist centers and will result in higher Medicare payments via
technology, it is expected that liver transplantation will rapidly
the cost report in programs (especially those with a high fraction of
adopt this promising technique. Many aspects of pulsatile perfu-
Medicare recipients). In addition, depending on contract language,
sion remain uncertain, however, and preparing proactively for its
there may be greater reimbursement from private payers that incor-
implementation will mitigate the clinical, regulatory, and financial
porate a separate payment for organ acquisition.
disruption that such innovative technology could cause. Without
Conversely, if the center that allocated the organ is responsible
proper planning and structured implementation, our patients may
for the cost of perfusion, this cost may be included in the clinical
not fully benefit from this technological advancement as cent-
cost of care. Only the center that chooses to use machine perfusion
ers will face economic disincentives to broader use. This white
will bear the cost of the device, and any payment will increase the
paper addresses potential key quality assurance, graft monitoring,
direct cost of the transplant. Although this may increase the volume
personnel training, data collection, and regulatory and financial
of transplants performed at the center, there is no provision in DRG
aspects of ex situ machine preservation and sets out recommen-
payments for greater reimbursement, unless the cost of machine
dations that can be embraced by transplant centers, policy makers,
perfusion leads to an outlier payment. Outlier payments, however,
and regulatory bodies. Not embracing these recommendations
are designed to reduce but not eliminate losses. A comparison may
could expose the field to disruption in a time where organ access
be made to desensitization treatments in kidney transplant, which in-
and efforts to improve organ sharing and allocation are at the
crease costs but do not necessarily result in greater payments either
center of the debate.
via the DRG or the cost report. Individual program finances would need to be scrutinized to determine whether this technology is financially feasible for small centers that perform fewer transplants.
10 | C A LL TO AC TI O N
An additional implication of transplant center cost allocation is a potentially inequitable distribution of the expense of perfusion.
The field of organ transplantation is witnessing the introduction
Whereas all centers benefit from an expansion of the organ supply
of one of its most important advancements in transplant tech-
and improved organ availability, only the centers that utilize the per-
nologies since the development of immunosuppression. Research
fusion devices bear the cost. Conversely, centers that take the risk
indicates that machine preservation may be far superior to the
and cost of incorporating perfusion into their practice may benefit
current standard preservation, a factor that will determine rapid
from higher volumes, lower rates of EAD, shorter ICU and hospital
adoption. Proactive engagement in all aspects of liver donation
stays, and improved patient outcomes.
and transplantation affected by ex situ machine preservation
Consequently, we suggest that once machine perfusion is FDA
will ensure maximum benefits of this technology, minimize un-
approved and off clinical trials, transplant centers and OPOs should
intended consequences, and improve access to a scarce and pre-
develop a mutually agreeable approach to perfusion in their dona-
cious resource.
tion service area. A regionalized preservation center administered by the OPO would allow broad amortization of the initial cost of the devices across multiple centers (rather than having each center purchase its own device) and incorporation of the cost of perfusion in
AC K N OW L E D G M E N T S The authors would like to thank the members of the initial discus-
the SAC cost rather than as a component of clinical care. In addition,
sion group at the ATC including Markus Selzner, David Reich, Luis
the cost of organs perfused, but discarded (a large volume in the
Fernandez, Stuart Knechtle, Sander Florman, and James Markmann.
UK studies), would not be absorbed by a single center if community-
We would also like to acknowledge the ASTS executive committee
based standard perfusion criteria could be established and endorsed
members who reviewed the manuscript.
by the regional centers. Furthermore, a central perfusion center eliminates the issue of the cost recovery from the new center should the organ be allocated when the initial recipient is unable to use the machine perfused organ.
D I S C LO S U R E The authors of this manuscript have conflicts of interest to disclose
Centers may also choose to retain control of the perfusion pro-
as described by the American Journal of Transplantation. Guarrera is a
cess, purchase and maintain the machines, and perform the perfu-
consultant to Organ Recovery Systems, Itasca, IL. The other authors
sion. This provides greater control, allows the center to choose which
have no conflicts of interest to disclose.
device is used, and ensures local control of all aspects of perfusion and timing. In this case, the transplant community should work to ensure that the incremental cost of the device is covered separately from routine clinical care by third-party payers to ensure that access to perfused organs is not restricted based on ability to pay.
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How to cite this article: Quintini C, Martins P, Shah S, et al. Implementing an innovated preservation technology: The American Society of Transplant Surgeons’ (ASTS) Standards Committee White Paper on Ex Situ Liver Machine Perfusion. Am J Transplant. 2018;00:1–10. https://doi.org/10.1111/ajt.14945
