THE USE OF MACHINE PERFUSION IN SURGICAL ONCOLOGY AND SPLIT LIVER TRANSPLANTATION

Abstract

Hepatobiliary surgical oncology and liver transplantation (LT) surgery have mutually benefited from their technological progresses and technical achievements of the last decade. The application of machine perfusion (MP) to ex-situ hepatectomies allows more patients with primary unresectable tumours to have access to radical treatment. Furthermore, the growing need for liver grafts for transplant purpose engaged surgeons in finding new solutions such as liver splitting during dynamic storage through MP to preserve the possibility of two LTs when in-situ splitting is not feasible.

Full text

Received: August 7, 2022
Accepted: September 30, 2022
Correspondence
Enrico Gringeri
Department of Surgery Oncology
and Gastroenterology, General Surgery 2
Hepatobiliary pancreatic surgery
and Liver Transplantation Unit, University
of Padua, via Giustiniani 2, 35128 Padua,
Italy. Tel.: +39 049 8218547.
E-mail: enrico.gringeri@unipd.it
How to cite this article: Gringeri E, Lanari J,
D’Amico FE, et al. The use of machine per-
fusion in surgical oncology and split liver
transplantation. EJT 2023;1:121-125. https://
doi.org/10.57603/EJT-014
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2023;1:121-125
DOI: 10.57603/EJT-014
Review
THE USE OF MACHINE PERFUSION IN
SURGICAL ONCOLOGY AND SPLIT LIVER
TRANSPLANTATION
Enrico Gringeri1, Jacopo Lanari1, Francesco Enrico D’Amico1,
Domenico Bassi1, Riccardo Boetto1, Alessandra Bertacco1, Annalisa Dolcet1,
Silvia Caregari1, Claudia Mescoli2, Paolo Feltracco3, Patrizia Burra4,
Umberto Cillo1
1Department of Surgery Oncology and Gastroenterology, General Surgery 2
Hepatobiliary pancreatic surgery and Liver Transplantation Unit, University
of Padua, Padua, Italy; 2Department of Medicine, Surgical Pathology
and Cytopathology Unit, University of Padua, Padua, Italy; 3Department of Medicine,
DIMED, Section of Anesthesiology and Intensive Care, University of Padua, Padua,
Italy; 4Department of Surgery Oncology and Gastroenterology, Multivisceral
Transplant Unit, University of Padua, Padua, Italy
Summary
Hepatobiliary surgical oncology and liver transplantation (LT) surgery
have mutually benefited from their technological progresses and technical
achievements of the last decade. The application of machine perfusion (MP)
to ex-situ hepatectomies allows more patients with primary unresectable tu-
mours to have access to radical treatment. Furthermore, the growing need
for liver grafts for transplant purpose engaged surgeons in finding new solu-
tions such as liver splitting during dynamic storage through MP to preserve
the possibility of two LTs when in-situ splitting is not feasible.
Key words: machine perfusion, liver tumours, hepatectomy, liver transplan-
tation, split liver
INTRODUCTION
The advent of machine perfusion (MP) represented a revolution in liver trans-
plantation (LT). The use of MP, either hypothermic or normothermic, have
been proved to restore marginal grafts to a state where they are deemed
transplantable and, consequently, allowing the overall donor pool to be ex-
panded 1-3. More recently, the idea of reconditioning the graft through MP
took place. In fact, the perfusion solution can be used as a medium for drugs,
antibodies and even cells, to modify the metabolism and physiology of the
perfused livers3.
Hepatobiliary surgical oncology took advantages of progress and achieve-
ments in LT. In 1988, Pichlmayr first described the so-called ex-situ liver
resection with complete removal of the liver from the body and resection as
a bench procedure, followed by auto-transplantation of the remnant liver4.
This pioneering procedure was developed to give the best therapeutic option
(namely, liver resection [LR]), to those patients affected by liver tumours for
which, due to the extension of the lesion or its location close to main vessels,
resection using conventional techniques is extremely difficult or even impos-
sible.

E. Gringeri et al.
122
MACHINE PERFUSION AND
EX-SITU
LIVER RESECTION
Definitely, ex-situ procedure and its variants wouldn’t be
possible without LT background5. A recent meta-analysis
on 224 reported patients who underwent ex-vivo liver
resection and auto-transplantation showed optimal re-
sults 6: for groups with malignant tumours, the 30-day
mortalities were 11.3%, and 1-year survivals were 65.0%;
when comparing those with malignant versus those with
nonmalignant lesions, major surgical complications oc-
curred in 50.0 vs 21.0%; p<.001. Moreover, one has to
bear in mind that for malignant indication no other cu-
rative option were available, at least since the advent of
Transplant Oncology.
From a technical point of view, the liver to be resected is
approached same as a graft during organ procurement
and hypothermic in situ perfusion is needed to preserve
liver parenchymal during total vascular exclusion (TVE)
phase. The seminal work described the cooling procedure
with the initial 10min perfusion of 8 L of Bretschneider
solution (histidine- tryptophan- ketoglutarate = HTK =
Custodiol) via portal vein and 200mL via hepatic artery.
Then the perfusion is repeated for about 5min after the
first 30min and every 60min of bench resection4. Dur-
ing anhepatic phase, temporary portocaval shunt and/or
extracorporeal venovenous bypass is required. Over time,
the same preservation solutions as in LT have been suc-
cessfully used and raised even the idea of adding cytopro-
tective agents, without confirmation of superiority over
standard solutions7-9. With the spread of the technique
in Europe and Japan, variations have been made but one
of the main objectives remains the correct preservation
of the liver during resection, and MP is the best available
technology for this purpose so far.
About 10 years ago, Authors’ group demonstrated
that ex-situ hepatectomy assisted by MP during bench
procedure is feasible in porcine model (Fig.1)10. Dur-
ing the last decade, fine-tuning of the procedure led to
our current approach with the adoption of hypothermic
oxygenated machine perfusion (HOPE). Compared to the
classic Pichlmayr procedure, performing bench hepa-
tectomy with HOPE assistance gives much more control
over future liver remnant preservation. Our experience
shows a good recovery of liver function after auto-
transplantation and a safe post-operative course for the
patient11. Mechanical perfusion of the liver could be use
also in the setting of ante situm procedure, that’s the
case with dissection of the suprahepatic inferior vena
cava only and hepatectomy performed inside patient’s
body. In such condition, the efficacy of conventional
cold flushing is questionable during prolonged in-vivo
TVE and given the uncertain hypothermic protection,
surgeons may be obliged to rush to avoid parenchymal
injury. Authors’ group recently published its technical
solution for ante situm procedure with HOPE assistance
(Fig.2)12. In summary, a machine perfusion system (Liv-
erAssist, Organ Assist, Groningen, The NetherlandsⒸ)
pumps the perfusate into an inflow cannula in the portal
vein. Perfusate is either recovered from an outflow can-
nula in a suprahepatic vein or suctioned from the abdo-
men and filtered through a cell saver (Fresenius CATSⒸ)
before being returned to the device for chilling and
oxygenation. The cannula length never exceeds 1.5m to
avoid increase in flow resistance. Celsior (IGLⒸ) is used
routinely both for static and HOPE organ preservation
for LT (also because of the low potassium content), al-
though several alternative preservation solutions exist.
Artery canulation is never performed to avoid vascular
intimal injury and reconstruction-related complications.
Available data are too sparse to draw a conclusion, but
one could postulate that HOPE may be associated with
more efficient and widespread diffusion of cold perfu-
sate and oxygen than cold flushing. Hence, MP during
Figure 1. Porcine ex-situ liver resection using machine perfusion (Padua experience).

MACHINE PERFUSION IN SURGICAL ONCOLOGY AND SPLIT LIVER TRANSPLANTATION 123
ante situm hepatectomies may extend the benefits seen
in LT to the field of surgical oncology.
The fertilization between surgical oncology and trans-
plantation is not only one way.
MACHINE PERFUSION AND SPLIT
LIVER TRANSPLANTATION
Technical refinements and technological upgrades (e.g.:
ultra-sound dissection devices), in the era of MP, brought
new life in the field of ex-vivo graft division for transplant
purpose, namely split-LT.
Split-LT is an important method that can increase the
available donor pool, however split livers are considered
marginal grafts per se because of their small size and
the variable degree of injury incurred due to splitting the
liver13. In-situ splitting, during the warm phase of organ
procurement, as several advantages over ex-vivo: shorter
cold ischemia time, easier identification of the bile duct
and vascular tissues, which results in a reduced inci-
dence of bleeding and bile leaks. However, in-situ split-
ting is not always feasible: it depends on local practice
and regulations, or donor couldn’t tolerate the procedure
due to hemodynamic instability. In such cases, ex-vivo
splitting is the first choice. To mitigate the risks linked
to this procedure, it was tested the division of the graft
during dynamic oxygenated storage.
Pre-clinical studies on animal model already showed that
MP, both normothermic and hypothermic, can be used for
liver preservation and splitting, without causing signifi-
cant graft damage14-16, and the concept was successfully
proved on discarded human liver17-19. In 2020, Spada et
al. reported the first case of human split-LT during dual
hypothermic oxygenated perfusion (DHOPE), and recipi-
ents of both extended right graft and hyper-reduced S2
graft experienced neither primary non-function (PNF)
nor ischemia-reperfusion injury (IRI) despite prolonged
ischemia times of 14 and 11 hours respectively20.
Early split experiences on discarded livers proposed
the use of normothermic machine perfusion (NMP) as a
method of viability assessment, logistical improvement,
and of potential benefit to the graft by reducing ischemia
times. However, liver splitting during NMP may add in-
creased risk of injury through additional rewarming steps,
increasing warm ischemia times, even more for extended
right lobe grafts traveling to another recipient hospital
in static cold storage. Finally, the theoretical advantage
of functional testing during NMP is not necessary for
high-quality grafts such as the ones that are eligible for
splitting. Indeed, HOPE has been preferred in subsequent
Figure 2. Ex-situ liver resection using machine perfusion (Padua experience).

E. Gringeri et al.
124
human case reports21-23. Rossignol et al.24 report the first
long series of prospectively performed ex-situ liver split-
ting during HOPE (HOPE-Split).
All partial grafts obtained after HOPE-Split were suc-
cessfully transplanted with a 90-day graft and recipient
survival of 100%. Compared to standard split, registered
liver graft-related adverse events (LGRAEs) were simi-
lar. Finally, HOPE-Split did not increase split procedure
duration but resulted in reduced static cold storage du-
ration leading to reduced IRI on reperfusion biopsies24.
With the aim of technical standardization of HOPE-Split
procedure, Authors agree with Rossignol et Al. that single
portal perfusion would be preferable over DHOPE. Portal
perfusion alone is easier to perform and allows to remove
one of the partial grafts from the device without interrupt-
ing the perfusion of the contralateral partial graft, no data
support the additional benefit of a dual perfusion com-
pared with a single perfusion25, and cannulation of the
branches of the hepatic artery might expose to arterial
injury (increased risk of intimal dissection).
CONCLUSIONS
In conclusion, the use of MP is revolutionizing both the
field of surgical oncology and split-LT allowing more and
more patients to have access to radical treatment for liver
tumours and end-stage liver disease.
Furthermore, MP is functional in the current time of
Transplant Oncology in the perspective of logistic or-
ganization of recipients for non-HCC indications. Pre-LT
abdominal inspection and frozen section analysis of hilar
lymph nodes are mandatory in transplant protocols for
both cholangiocarcinoma and colorectal liver metastases.
Hence, hepatectomy time is inevitably increased or, in the
worst scenario, recipient might be changed because of
finding of extra-hepatic spreading of the disease. Dynamic
storage of graft allocated to such recipients have to be
preferred over static, allowing the best graft preserva-
tion, and reconditioning in cases of expected prolonged
ischemia time2,26-28.
Conflict of interest statement
The Authors declare no conflict of interest.
Funding
This research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-
profit sectors.
Authors’ contributions
EG, JL: wrote the paper; FED, DB, RB, AB, AD, SC: per-
formed the literature review; CM, PF, PB, UC: critically
revised the paper.
Ethical consideration
This is a review paper. For each study cited in the text the
research was conducted ethically, with all study proce-
dures being performed in accordance with the require-
ments of the World Medical Association’s Declaration of
Helsinki. Written informed consent was obtained from
each participant/patient for study participation and data
publication.
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