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FEATURE
Normothermic Perfusion
A New Paradigm for Organ Preservation
Jens Brockmann, MD,*¶ Srikanth Reddy, FRCS,* Constantin Coussios, PhD,‡ David Pigott, FRCA,§
Dino Guirriero, MPhil,* David Hughes, PhD,¶ Alireza Morovat, PhD,储Debabrata Roy, FRCS,*¶
Lucy Winter, MBBS,** and Peter J. Friend, MD, FRCS*¶
Objective: Transplantation of organs retrieved after cardiac arrest could
increase the donor organ supply. However, the combination of warm isch-
emia and cold preservation is highly detrimental to the reperfused organ. Our
objective was to maintain physiological temperature and organ function
during preservation and thereby alleviate this injury and allow successful
transplantation.
Background Data: We have developed a liver perfusion device that main-
tains physiological temperature with provision of oxygen and nutrition.
Reperfusion experiments suggested that this allows recovery of ischemic
damage.
Methods: In a pig liver transplant model, we compared the outcome
following either conventional cold preservation or warm preservation. Pres-
ervation periods of 5 and 20 hours and durations of warm ischemia of 40 and
60 minutes were tested.
Results: After 20 hours preservation without warm ischemia, post-transplant
survival was improved (27%– 86%, P⫽0.026), with corresponding differ-
ences in transaminase levels and histological analysis. With the addition of
40 minutes warm ischemia, the differences were even more marked (cold vs.
warm groups 0% vs. 83%, P⫽0.001). However, with 60 minutes warm
ischemia and 20 hours preservation, there were no survivors. Analysis of
hemodynamic and liver function data during perfusion showed several
factors to be predictive of posttransplant survival, including bile production,
base excess, portal vein flow, and hepatocellular enzymes.
Conclusions: Organ preservation by warm perfusion, maintaining physio-
logical pressure and flow parameters, has enabled prolonged preservation
and successful transplantation of both normal livers and those with substan-
tial ischemic damage. This technique has the potential to address the shortage
of organs for transplantation.
(Ann Surg 2009;250: 1– 6)
Refrigeration is the scientific principle, which underpins the cur-
rent clinical practice of preservation of living tissue for organ
transplantation. Cooling slows metabolic processes and prolongs the
time during which the organ can be deprived of oxygen without loss
of viability. However, energy consumption due to metabolic activity
is not halted but reduced (approximately 12-fold) by cooling to ice
temperature and, ultimately, the limitation of cold storage is deter-
mined by mitochondrial damage consequent upon ATP depletion.
Cooling also has direct deleterious effects on plasma membrane
lipids, cytoskeleton, microtubules, and mitochondria,
1
with the ef-
fect of disabling the ion-exchange pumps in the cell membrane
causing swelling and cell lysis. Donor organs are therefore perfused
with specialist preservation solution, the primary function of which
is to reduce cell swelling and maintain physiological intracellular
ionic composition.
2
Cold preservation has served the needs of organ transplanta-
tion well for over 4 decades— kidneys can be transplanted success-
fully after cold preservation times in excess of 24 hours, although
the limits for other organs are less. However, preservation is in-
creasingly seen as the limiting technology in the further develop-
ment of transplantation—there are several reasons for this. First,
there is an absolute limit to the duration of cold preservation.
Second, preservation damage is a direct function of preservation
time
3
and, contrary to earlier belief, a cause of long-term progressive
graft damage even in organs that initially recover function.
4
Third,
there is no reliable means of assessing viability of an organ imme-
diately prior to transplantation.
5
Finally, increasing demand now
necessitates that organs are transplanted from donors that would
once have been declined. Such organs tolerate cold preservation
injury poorly.
6
Conventionally, an organ donor is a patient who has sustained
a catastrophic brain injury, in whom (brain) death is diagnosed on
neurologic criteria while the heart is functioning—the circulation is
maintained until the moment the organs are perfused with cold
preservation solution and removed. Organs for transplantation can
be retrieved with little or no warm ischemia time from such “heart-
beating” donors (HBD). For increasing numbers of patients dying of
brain injury, however, the terminal event is a cardiac arrest. Under
some circumstances it is possible to retrieve organs quite rapidly
after death—particularly from patients in hospital in whom death is
predicted—although with still-significant periods of warm ischemia.
Such “non– heart-beating” donors (NHBD) already provide an in-
creasing number of kidneys for transplantation although, even with
warm ischemia times limited to 30 minutes, these organs have a very
high incidence of delayed function caused by acute tubular necro-
sis.
7
Liver transplantation has also been carried out with organs from
NHBD, but with even more restricted warm ischemia times— unlike
the kidney patient, who can be dialyzed, delayed graft function
cannot be tolerated in a liver transplant recipient.
6,7
Furthermore,
even in these very selected cases, the reported results of transplan-
tation of NHBD livers are inferior to those of HBD organs.
8
Even with the most effective preservation solution, cold
storage leads to immediate graft injury at the time of transplantation.
This is due to 2 processes, one proportional to the duration of
ischemia
3
and the other related specifically to cooling.
1,9,10
The
major component of preservation injury is caused by reactive oxy-
gen species (ROS), which are generated at the time of reintroduction
From the *Nuffield Department of Surgery, University of Oxford, Oxford, United
Kingdom; ‡Department of Biomedical Engineering, University of Oxford,
Oxford, United Kingdom; §Department of Anaesthesia, John Radcliffe Hos-
pital, Oxford, United Kingdom; ¶Oxford Transplant Centre, Churchill Hos-
pital, Oxford, United Kingdom; 㛳Department of Clinical Biochemistry, John
Radcliffe Hospital, Oxford, United Kingdom; and **Department of Pathol-
ogy, John Radcliffe Hospital, Oxford, United Kingdom.
Supported by the Welcome Trust grant (073394/z/03/z).
Reprints: Peter J Friend, MD, FRCS, Nuffield Department of Surgery, John
Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom. E-mail: Peter.friend@
nds.ox.ac.uk.
Copyright © 2009 by Lippincott Williams & Wilkins
ISSN: 0003-4932/09/25001-0001
DOI: 10.1097/SLA.0b013e3181a63c10
Annals of Surgery • Volume 250, Number 1, July 2009 www.annalsofsurgery.com |1
of oxygen to ischemic tissue.
10,11
A number of mechanisms underlie
the over-production of ROS—these include metabolism of hypoxan-
thine (a metabolic product of ATP),
12
calcium overload within
mitochondria,
13,14
and neutrophils recruited as a consequence of
adhesion molecules, cytokine release, and complement activation.
15
ROS create oxidative damage to the mitochondrial electron-trans-
port chain and peroxidation of lipids, proteins, and DNA.
16–18
This
injury is magnified by the direct effect of hypothermia.
19
THEORY OF WARM PRESERVATION
Organ preservation by warm perfusion is based on the hy-
pothesis that preservation injury can be minimized by avoiding both
cooling and hypoxia. This requires the delivery of oxygen, nutrients,
and maintenance of normal body temperature to allow normal
physiological metabolism to continue during organ storage.
The work described in this article is based on preservation of
the liver, but is likely to be applicable to other organs. The pig is a
model that is both rigorous (a lower tolerance of preservation injury
than the human
20
) and clinically-relevant (pig organs are similar in
size and anatomy to the human). Thus, technology developed in the
pig is likely to be suitable for clinical use.
We have previously described the use of a warm perfusion
circuit designed for the porcine liver, which provides oxygenated
blood and nutrients to the liver through the portal vein and hepatic
artery at physiological pressures and flows. Initial studies showed
maintenance of metabolic and synthetic functions of the liver with
well-preserved histologic appearances over a 72-hour period of
isolated perfusion.
21
Warm perfusion was then compared with cold
storage in a model of liver preservation—livers were stored for 24
hours either in University of Wisconsin solution (the clinical stan-
dard) or on the perfusion circuit. All livers were then reperfused on
the circuit as a surrogate for transplantation. Measurement of met-
abolic and synthetic function as well as hepatocellular injury showed
significant advantage to the warm perfusion system,
22
and this was
confirmed by histologic assessment. These experiments were then
repeated with the addition of 60 minutes of warm ischemia before
preservation and even greater differences were noted.
23
Whereas all
parameters in the warm-preserved group were similar to the previ-
ous study, in the cold-preserved group, there was hemodynamic
evidence of a severe ischemia-reperfusion injury and no bile pro-
duction or evidence of glucose consumption. A subsequent study
showed that much of the damage associated with cold preservation
occurs with a much shorter period of cold storage of 4 hours.
24
Successful transplantation of the porcine liver after 60 minutes of
warm ischemia has been achieved without preservation and also
following 4 hours of normothermic preservation, but not with cold
preservation.
25
However, for warm preservation of NHBD organs to
be a viable therapeutic technique, much longer preservation times
are needed.
The studies described in this article were carried out to test
whether the results of the reperfusion studies described above can be
translated into a liver transplant model. This is an essential prelude
to any trial of warm preservation in clinical liver transplantation. We
therefore asked the following questions:
• Is warm perfusion as effective as cold storage in transplantation of
livers from HBD preserved for a modest period?
• Can the duration of safe preservation of HBD livers be extended
using warm perfusion?
• Does warm perfusion allow safe transplantation of livers after
prolonged warm ischemia followed by extended preservation?
• Are hemodynamic and functional parameters measured during
warm perfusion predictive of which livers will function and which
will fail after transplantation?
MATERIALS AND METHODS
White Landrace pigs (40 –50 kg) were used and treated in
accordance with the United Kingdom Animal Protection Act 1986.
Livers were retrieved using a standard technique under general
anesthesia. Cold preserved livers were flushed and stored with
University of Wisconsin solution at ice temperature, according to
standard clinical practice. Warm preserved livers were flushed with
cold preservation solution and remained cold during a 45 to 60
minute back-table preparation before connection to the circuit for
normothermic perfusion. For experiments involving warm ischemia,
the liver was dissected before inducing cardiac arrest (intravenous
potassium chloride), then left in situ during the period of warm
ischemia before cold-flushing followed by preservation (cold or
normothermic).
Experimental groups (Table 1) were based on the following
variables:
• Duration of warm ischemia before retrieval (minimal, 40 minutes,
60 minutes).
• Mode of preservation (cold or warm).
• Duration of preservation (5 or 20 hours).
Normothermic perfusion was performed as previously de-
scribed.
21
The perfusion circuit was constructed using pediatric
cardiopulmonary bypass components and incorporates a centrifugal
pump (BP50, Medtronic), hollow fiber membrane oxygenator (hol-
low fiber membrane oxygenator 2000, Jostra AG, Hirrligen, Ger-
many) and soft-shell reservoir (MVR– 800, Medtronic). The design
provides dual perfusion of hepatic artery (directly from the pump)
and portal vein (via the reservoir) at physiological pressures. It
allows autoregulation of the blood flow through the liver, with
constant arterial pressure at variable flow rates.
The circuit was primed with 1.5 liter of autologous blood and
anticoagulated with heparin. At the start of perfusion, an initial
acidosis was corrected with sodium bicarbonate but no correction
was made thereafter. Bile production was measured hourly and
perfusate samples collected. Gas flows were adjusted to maintain
blood gases within physiological ranges. Prostacyclin (Flolan, Glaxo
Wellcome, Middlesex, United Kingdom) at 8
g/h and 2% tauro-
cholic acid (Sigma, United Kingdom) at 7 mL/h were infused and
bolus doses of 5000 units heparin given every 4 hours. Nutrition was
provided by an infusion of essential amino acids (Nutriflex lipid
plus, B. Braun Melsungen AG, Germany) at 15 mL/h.
Recipient animals were premedicated with ketamine and
midazolam. Anesthesia was induced and maintained with intrave-
TABLE 1. Group Sizes and Nomenclature
Warm Ischaemia
5 h Preservation 20 h Preservation
Cold (n) Warm (n) Cold (n) Warm (n)
Minimal (HBD) C5-HBD (5) W5-HBD (5) C20-HBD (7) W20-HBD (7)
40 min (NHBD) — — C20-NHBD40 (4) W20-NHBD40 (6)
60 min (NHBD) — — — W20-NHBD60 (4)
Brockmann et al Annals of Surgery • Volume 250, Number 1, July 2009
2| www.annalsofsurgery.com © 2009 Lippincott Williams & Wilkins
nous propofol. Central venous and arterial lines and a urinary
catheter were placed. Orthotopic liver transplantation was carried
out via a midline abdominal incision. A Carmeda-bonded passive
bypass was placed from the splenic vein to the external jugular vein
(Medtronic, Grand Rapids, MI) during the anhepatic phase. The
liver was reperfused through the portal vein before anastomosing the
hepatic artery. Postoperative cyclosporine and steroids were given
for immunosuppression. Experiments were terminated at 5 days.
The following laboratory analyses were performed:
Biochemistry
Markers of hepatocellular injury (AST, ALT)-automated an-
alyzer (Abbott Aeroset, Maidenhead, United Kingdom). Sinusoidal
endothelial cell injury (SEC) injury, hyaluronic acid (HA)—sand-
wich enzyme-linked immunosorbent assay method (Corgenix Inc.,
Peterborough, United Kingdom).
Histopathology
Biopsies taken at donor hepatectomy, the end of preservation,
1 hour after reperfusion, and at autopsy were stained with hematox-
ylin and eosin, and examined for necrosis, hemorrhage, cholestasis,
and sinusoidal dilatation. Each parameter was evaluated separately
and scored by a pathologist blinded to the groups (Table 2).
Immunohistochemistry
Apoptosis was assessed by identifying Caspase-3 positive
hepatocytes by the alkaline phosphatase-antialkaline phosphatase
(APAAP) technique. For this, a primary antibody (rabbit polyclonal
antiactive caspase 3, G748, Promega Corporation, Madison, WI),
secondary antibody (mouse anti-rabbit IgG, M0737, Dakocytoma-
tion, Glostrup, Denmark), tertiary antibody (rabbit antimouse anti-
body, Z0259, Dakocytomation), and mouse APAAP (D0651, Da-
kocytomation) were used. Twenty random high power fields were
assessed for each section. The Caspase-3 assay was used in prefer-
ence to the TUNEL assay in these experiments as the former is
known to over-estimate the degree of apoptosis in the presence of
necrosis.
26
Statistical Analysis
Performed on SPSS software (SPSS 13.0; SPSS Inc, Chicago,
IL). Sample sizes were calculated to detect a difference in survival
at a 5% significance level with 80% power. Log-rank test,
repeated measures analysis of variance and the Mann-Whitney U
test were used.
RESULTS
Animal Survival
At 5 hours preservation, there was no difference in survival
with cold compared with warm preservation of HBD organs (Table
3; Fig. 1). At 20 hours preservation, there was a significant advan-
tage in warm compared with cold preservation of both heart-beating
(P⫽0.026) and 40 minute warm ischemia NHBD (P⫽0.001)
organs. In the 20 hour warm-preserved groups, there was no differ-
ence in survival of recipients of heart-beating compared with NHBD
(40 minute warm ischemia) organs (86% vs. 83%, P⫽0.86). There
were no survivors after transplantation of 60 minute warm ischemia
NHBD organs.
Cellular Injury
HBDs, 5 Hours Preservation (Groups C5-HBD,
W5-HBD)
There was no significant difference between the warm and
cold-preserved groups:
AST (P⫽0.29), ALT (P⫽0.17), HA levels (P⫽0.51)
(Figs. 2A, B).
HBDs, 20 Hours Preservation (Groups C20-HBD,
W20-HBD)
There were significantly higher levels of enzyme release in
the cold preserved group:
AST (P⫽0.02), ALT (P⫽0.06).
The differences in HA levels were not statistically significant
(P⫽0.461).
NHBD, 40 Minutes Warm Ischemia 20 Hours
Preservation (Groups C20-NHBD40, W20-NHBD40)
There were significantly higher levels of enzyme release in
the cold perfusion group: AST (P⫽0.001), ALT (P⫽0.001).
Histology and Immunohistochemistry (Fig. 3)
There were no differences between the 5-hour preservation
groups. In the 20-hour HBD groups, hemorrhage and necrosis scores
(1.96 ⫾0.2 vs. 0.8 ⫾0.2, P⫽0.04) and the number of apoptotic
cells (11% ⫾3.6% vs. 1.6 ⫾0.3, P⫽0.03) were significantly
higher at autopsy in the cold preservation group.
TABLE 2. Scoring System Used by a Pathologist Who Was
Blinded to the Treatment Protocols
Score Haemorrhage Necrosis Cholestasis Sinusoidal Dilatation
0 Absent Absent Absent None
1 Focal Pericentral Present Mild
2 Zonal Zone 2 ⫹3 — Moderate
3 Pan-lobular Pan-lobular — Severe
TABLE 3. Recipient Outcomes, Analyzed by Log Rank Test
Group (n) Survival Reason for Nonsurvival (n) P
C5-HBD (5) 4 (80%) Technical (1)-bilateral
pneumothorax
0.80
W5-HBD (5) 4 (80%) Technical (1)-bile duct injury
during retrieval
C20-HBD (7) 2 (27%) Liver failure (5) 0.026
W20-HBD (7) 6 (86%) Technical (1)-air embolism
C20-NHBD40 (4) 0 Liver failure (4) 0.001
W20-NHBD40 (6) 5 (83%) No cause on autopsy (1)
W20-NHBD60 (4) 0 Liver failure (4)
FIGURE 1. Recipient survival of different experimental
groups preserved for 20 hours.
Annals of Surgery • Volume 250, Number 1, July 2009 Normothermic Perfusion of Porcine Livers
© 2009 Lippincott Williams & Wilkins www.annalsofsurgery.com |3
In the 40 minute warm ischemia 20-hour NHBD groups, the
extent of hemorrhage and necrosis at autopsy was much lower in the
warm preserved livers (1.8 ⫾0.2 vs. 0.4 ⫾0.2, P⫽0.03).
Compared with the reperfusion biopsy, there was a large increase in
apoptotic cells in cold group but a significant decrease in the warm
group (15% ⫾5% vs. 1.1% ⫾0.5%, P⫽0.01). Livers in the 60
minute warm ischemia warm preserved group showed extensive
necrosis and apoptosis at the end of preservation and thereafter.
Predictive Values of Perfusion Parameters
To develop an algorithm to use perfusion parameters to
predict posttransplant function, we decided to compare those livers
that did not develop liver failure after transplantation with those that
did (Table 4). Thus, the “successful” groups (W20-HBD and W20-
NHBD40) were compared with the “unsuccessful” W20-NHBD60
group, using repeated measures analysis. For all parameters shown,
significant differences were identified no later than 4 hours from the
start of perfusion.
DISCUSSION
Normothermic perfusion is a logical approach to problems
that are inherent in organ transplantation. Maintenance of metabolic
function during preservation avoids depletion of cellular energy
stores, the build-up of metabolic products, and the direct effects of
cooling. It allows the function of the organ to be assessed during
storage and thereby may enable more “marginal” organs to be
transplanted.
27
As well as limiting preservation injury, it may
actually allow resuscitation of injury sustained before retrieval,
including warm ischemic damage. It may also allow organ-specific
FIGURE 2. Postoperative transaminase levels in
HBD and NHBD liver recipients. A, Postoperative
AST levels in HBD (minimal warm ischemia) livers
preserved for 20 hours. Mean ⫾SEM (normal
range: 14– 43 U/L, P⫽0.02 by repeated mea-
sures analysis). B, Postoperative AST levels in
NHBD (40 minutes warm ischemia) livers pre-
served for 20 hours. Mean ⫾SEM (P⫽0.001 by
repeated measures analysis). All animals in the
cold group died within 4 hours of transplantation.
FIGURE 3. Histologic scoring of hemorrhage and
necrosis. Histologic findings were evaluated at in-
dicated time points in the experimental groups.
The severity of these changes was evaluated by a
semiquantitative scoring system using criteria out-
lined in Table 2. Data expressed as the median
value ⫾SEM.
TABLE 4. Prediction of Posttransplant Viability by
Hemodynamic and Functional Parameters During
Normothermic Preservation at 16 Hour
Successful
(n ⴝ13)
Unsuccessful
(n ⴝ4) P
Bile output (mL/h) 11.4 ⫾1.4 2.8 ⫾1.0 0.003
Base excess (mEq/L) 3.3 ⫾1.7 ⫺11.6 ⫾3.0 0.02
AST (IU/L) 964 ⫾302 3198 ⫾677 0.01
ALT (IU/L) 62 ⫾10 223 ⫾75 0.015
HA (ng/ml) 108 6078 0.006
Portal pressure (mmHg) 2.5 ⫾1 11.7 ⫾2.0 0.006
Portal venous resistance 1.6 ⫾0.9 35.4 ⫾17.3 0.006
Brockmann et al Annals of Surgery • Volume 250, Number 1, July 2009
4| www.annalsofsurgery.com © 2009 Lippincott Williams & Wilkins
gene therapy interventions to enhance the outcome following trans-
plantation.
28
The potential advantages of normothermic perfusion have
been apparent to investigators for many years. However, the liver is
notoriously difficult to maintain in isolation and previous investiga-
tors have failed to maintain a stable perfusion for more than 24
hours
29,30
The circuit used for the experiments described here is
novel insofar as it allows “autoregulation” of the hepatic arterial
flow. The outflow from the pump bifurcates to supply the hepatic
artery directly and the portal vein via an adjustable resistance and a
variable capacity reservoir—this effectively acts as a partial arterial
bypass and allows the hepatic artery to be perfused at constant
pressure but variable flow rate.
The 5-hour experiments confirmed that the underlying con-
cept of normothermic preservation is sound. Subsequent 20-hour
experiments, substantially beyond the limit of the conventional cold
preservation technology, corroborated the previous reperfusion stud-
ies carried out by our group.
22
We have not established the limit of
normothermic preservation— unlike cold storage, progressive dete-
rioration of the organ is not inevitable and the ultimate limit is more
likely to be related to mechanical damage to blood components and
vessels than to cellular metabolic events.
The 40 and 60 minute periods of warm ischemia are consid-
erably longer than would be acceptable in current clinical practice.
At present, almost all clinical NHBD liver transplants are carried out
using organs from “controlled” NHBD—patients in whom cardiac
arrest is predicted because life-supporting treatment has been with-
drawn.
6
This enables very short warm ischemia times (from cardiac
arrest to cooling)— often no more than 15 minutes— but the logis-
tics are complex, excluding many potential donors.
A more liberal warm ischemia policy (40 minutes or more)
would enable organs to be retrieved and transplanted from a much
wider spectrum of donors, including those who are declared dead in
an Emergency Department following unsuccessful cardiopulmonary
resuscitation. Such “uncontrolled” NHBD constitute a very large
potential source of donor organs which would have a massive
impact on the shortage of organs for transplantation.
31
The results of the warm ischemia (NHBD) transplant exper-
iments described here also corroborate our previous reperfusion
studies
23
and provide evidence that the use of normothermic pres-
ervation might allow organs to tolerate a prolonged warm ischemic
injury. Importantly, this does not appear to come at a high price in
terms of postoperative morbidity—the outcome following transplan-
tation was as good in recipients of 40 minute warm ischemia
“NHBD” organs as in “HBD” organ recipients with minimal warm
ischemia. Clearly, the 5-day follow-up period did not enable assess-
ment of longer-term complications, particularly the biliary strictur-
ing, which is now associated with prolonged preservation and warm
ischemia in both clinical
32
and experimental studies.
33
The potential of viability testing is of great importance in the
clinical setting. While deleterious to long-term outcome in kidney
transplantation, delayed function of a liver transplant is a disaster.
For this reason, if there is real uncertainty as to whether a particular
organ is viable, the ethical responsibility of the surgeon is to follow
the best interests of the individual patient (who is likely to receive a
subsequent and lower-risk offer) and reject the organ. The lack of an
effective means of assessment undoubtedly has the effect that many
livers that would have functioned are not transplanted.
Despite this concern, with increasing demand, livers which
once would have been discarded are now being considered for
transplantation. These “marginal” livers include organs from donors
with serious medical comorbidities (cardiovascular disease, obesity,
diabetes), livers damaged by fat deposition within the hepatocytes,
and those from NHBD.
32,34
Preoperative biochemistry, visual in-
spection or histology do not reliably predict those livers that will fail
after transplantation.
5
If non– heart-beating and other marginal do-
nors are to have a major impact on transplantation, then a reliable
means of predicting function is essential.
By comparing the perfusion characteristics of those warm-
preserved livers, which subsequently developed liver failure after
transplantation (W20-NHBD60) with those that functioned after
transplantation (W20-HBD and W20-HBD40), it is clear that there
are easily-measured perfusion parameters which reliably predict
function after transplantation.
We believe that the restoration and maintenance of cellular
energy stores and mitochondrial function (unpublished data) are
central to the mechanism by which warm perfusion prevents the
harmful effects of preservation. The optimal approach to the NHBD
might include immediate in situ perfusion with oxygenated blood,
“normothermic recirculation,”
35
before retrieval and subsequent
normothermic preservation.
Notwithstanding the need to understand the mechanisms in
greater detail, we believe that the benefits shown in this preclinical
model are sufficient to warrant a clinical trial. Normothermic pres-
ervation is complex and inherently more expensive than cold pres-
ervation. For this technique to become established in clinical prac-
tice, it will be necessary to demonstrate not only functional benefit
over conventional preservation, but also that it can lead to a
sustainable increase in the number of donor livers that can be
transplanted. The studies presented here provide compelling evi-
dence that normothermic preservation might be the means to unlock
a large new source of donor organs; this would be a vital component
in a strategy to provide transplantation for all patients in need.
ACKNOWLEDGMENTS
The authors thank for the assistance of the following in
carrying out the studies presented: Andrew Butler, Shantanu Bhat-
tacharyja, Sue Fuggle, Joanne Greenwood, Ashok Handa, Tim
James, Nikolai Maniakin, Juan Piris, Andrew Sutherland, Richard
Taylor, Feng Xia, and Miguel Zilvetti.
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