Irreversible Electroporation of the Liver and Liver Hilum in Swine

Article (PDF Available)inHPB 13(3):168-73 · March 2011with22 Reads
DOI: 10.1111/j.1477-2574.2010.00261.x · Source: PubMed
Abstract
Irreversible electroporation (IRE) is a novel, non-thermal form of ablation. We studied the safety and efficacy of IRE for the ablation of liver tissue around the liver hilum. We also studied the ability of triphenyltetrazolium chloride staining (TTC) to predict the zone of ablation after IRE. Eight swine underwent 20 ablations of the liver and liver hilum. Two monopolar probes were positioned 2 cm apart. IRE was performed using 90 pulses of 2500-3000 V/cm. IRE treatments were performed from 15 min to 14 days (n= 4) before sacrifice. All animals survived. No major complications were encountered. Ablation width ranged from 2.27 to 4.45 cm and ablation height ranged from 1.5 to 1.8 cm. TTC staining demonstrated the zone of ablation in all animals. Hepatocyte necrosis occurs immediately adjacent to large central veins without evidence of heat sink. Bile ducts, portal veins and hepatic arteries appear to be more resistant to the effects of IRE. IRE appears to be safe and effective for liver tissue ablation in the liver hilum. The portal structures appear more resistant to the effects of IRE. TTC staining can predict the zone of IRE ablation as early as 15 min after treatment.
ORIGINAL ARTICLE
Irreversible electroporation of the liver and liver hilum in swine
Kevin P. Charpentier
1
, Farrah Wolf
2
, Lelia Noble
3
, Brody Winn
3
, Murray Resnick
3
& Damian E. Dupuy
2
Departments of
1
Surgery,
2
Radiology and
3
Pathology, Rode Island Hospital and the Warren Alpert School of Medicine at Brown University, Providence, RI,
USA
Abstracthpb_261 168..173
Background: Irreversible electroporation (IRE) is a novel, non-thermal form of ablation. We studied the
safety and efficacy of IRE for the ablation of liver tissue around the liver hilum. We also studied the ability
of triphenyltetrazolium chloride staining (TTC) to predict the zone of ablation after IRE.
Methods: Eight swine underwent 20 ablations of the liver and liver hilum. Two monopolar probes were
positioned 2 cm apart. IRE was performed using 90 pulses of 2500–3000 V/cm. IRE treatments were
performed from 15 min to 14 days (n = 4) before sacrifice.
Results: All animals survived. No major complications were encountered. Ablation width ranged from
2.27 to 4.45 cm and ablation height ranged from 1.5 to 1.8 cm. TTC staining demonstrated the zone of
ablation in all animals. Hepatocyte necrosis occurs immediately adjacent to large central veins without
evidence of heat sink. Bile ducts, portal veins and hepatic arteries appear to be more resistant to the
effects of IRE.
Conclusions: IRE appears to be safe and effective for liver tissue ablation in the liver hilum. The portal
structures appear more resistant to the effects of IRE. TTC staining can predict the zone of IRE ablation
as early as 15 min after treatment.
Keywords
liver, tumour, ablation, electroporation
Received 3 June 2010; accepted 9 October 2010
Correspondence
Kevin P. Charpentier, University Surgical Associates, 2 Dudley St., Suite 470, Providence, RI 02905, USA.
Tel: +1 401 228 0560; Fax: +1 401 228 0636; E-mail: kcharpentier@lifespan.org
Introduction
Thermal ablation is a proven and effective therapy for the treat-
ment of selected primary and metastatic tumours of the liver.
Thermal ablation can be achieved using radiofrequency ablation
(RFA) or microwave ablation (MWA). Complete pathological
response rates for liver tumours <3 cm in size are as high as 65%
with RFA.
1,2
Similar results can be achieved with MWA.
3
Thermal ablation relies on the ability to heat the target tissue
to 60°C for instantaneous cell death. Cell death is less reliable at
lower temperatures and requires longer exposure at the target
temperature.
4
Heat sink represents a major limitation of thermal
ablation.
5
Heat sink refers to the loss of heat at the tissue level as
a result of adjacent circulating blood of a cooler temperature.
Tumours adjacent to the hepatic veins, large portal veins and
inferior vena cava are at greatest risk for incomplete tumour
necrosis and local recurrence because of heat sink. Another
limitation of thermal ablation is the risk of collateral
damage to healthy, vital structures adjacent to the tumour being
ablated.
Irreversible electroporation (IRE) is a novel, non-thermal abla-
tion technology that utilizes short pulses of high frequency elec-
trical energy to ablate tissue.
6
IRE is performed by placing
electrodes into the tissue and delivering 90 pulses of 1000–
3000 V/cm DC energy between the electrodes. Cell death is initi-
ated via the creation of micropores in the cell membrane.
Previous pre-clinical studies in swine liver demonstrate the
ability of IRE to ablate tissue immediately adjacent to large venous
structures without evidence of heat sink.
6,7
Because the location
of IRE activity is the cell membrane, acellular structures are
preserved.
This work was supported by a research grant from Angiodynamics, Queens-
bury, NY.
This abstract was presented as a poster at the Society for Surgical Oncology
Annual Meeting in St. Louis, MO, March 2010.
DOI:10.1111/j.1477-2574.2010.00261.x
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Unlike thermal ablation, cell death after IRE is not instanta-
neous. Triphenyltetrazolium chloride (TTC) staining has been
shown to predict the area of irreversible myocardial ischaemia
before histological evidence of cell death using haematoxylin and
eosin (H&E) staining.
8
The aim of the present study was to evaluate the feasibility and
safety of creating IRE ablations in liver tissue around the liver
hilum and to compare liver hilum ablations to intra-hepatic liver
ablations. Additionally, we studied the ability of TTC staining to
predict the zone of IRE ablation.
Methods
This study was approved by our institutional animal care and use
committee.
General anaesthesia was induced in four domestic female swine
using glycopyrrolate 0.003 mg/kg intramuscularly (i.m.), telazol
5 mg/kg i.m., xylazine 2 mg/kg i.m. and sodium thiopental
20 mg/kg intravenously (i.v.) as needed. Animals were intubated
to facilitate mechanical ventilation. General anaesthesia was
maintained with 2–4% isoflurane in oxygen. Pre-emptive analge-
sia was administered using buprenorphine 0.03 mg/kg i.m.
Adequacy of anaesthesia was determined using jaw tone and pedal
reflex. Anaesthesia was increased if a response to stimuli was
noted. A baseline-evoked motor response was obtained with a
nerve stimulator positioned near the ulnar nerve. Animals were
monitored intra-operatively using telemetry and pulse-oximetry.
The abdominal wall was prepared using betadine scrub and
solution. Before incision, animals received a single dose of ceph-
azolin 40 mg/kg i.v. An 8-cm incision was made in the upper
midline and the peritoneal cavity entered. Pancuronium
0.1 mg/kg was administered to achieve reversible paralysis as
monitored by an evoked motor response.
A portal triad entering the liver hilum was identified and
mono-polar IRE electrodes were positioned within the liver
parenchyma, 2 cm apart, on either side of the portal triad. The
active portion of the electrodes was exposed for a length of 2 cm.
Probe positioning was confirmed by intra-operative ultrasound.
Three thousand volts/cm was delivered between the electrodes in
100 microsecond pulses. Ninety pulses were delivered per abla-
tion. The pulses are delivered in groups of ten with an intervening
250 mSec pause which allows the capacitor to recharge according
to the manufacturer’s treatment software (Nanoknife, Angiody-
namics, Queensbury, NY). The polarity of the electrodes was then
reversed without repositioning and the treatment was repeated
using the same parameters in the same anatomic location with
reverse polarity.
A remote segment of the left, lateral liver was then treated using
the same technique and parameters in an intra-hepatic location
remote from the liver hilum.
The muscle relaxation was reversed using neostigmine 0.044–
0.066 mg/kg i.v. and atropine 0.005 mg/kg i.v. Animals were
recovered. Post-operative pain control was achieved using a fen-
tanyl transdermal patch 75 mcg/h and tramadol 150 mg by mouth
twice daily for 3 days and as needed.
Phlebotomy for liver serum chemistries was performed pre-
procedure while under anaesthesia and on post-operative days 2
and 5 for surviving animals.
Animals survived for 2 h (n = 1),2days(n = 1) and 14 days (n
= 2). Once the target survival time was reached, animals were
anaesthetized as previously described and euthanasia performed
with pentobarbital 100 mg/kg. A laparotomy was performed and
the liver and extra-hepatic portal structures were recovered.
The area of ablation was sectioned at 5-mm intervals for gross
evaluation. The 5-mm section in the centre of the ablation cavity
was stained with triphenyltetrazolium chloride. The remaining
sections were fixed in formalin. Height and width of ablation
cavities were measured. Histological analysis was performed after
H&E staining of 6–8 micron sections.
An additional four female domestic swine were subjected to
general anaesthesia and chemical paralysis as previously
described. IRE of the pancreatic head was performed as part of a
separate protocol and the results have already been reported.
9
Animals were recovered as previously described and survived for
2h(n = 1),2days(n = 1) and 2 weeks (n = 2). Before euthanasia,
animals were subject to general anaesthesia as previously
described. IRE was performed at three separate sites within the
liver parenchyma 1 h, 30 min and 15 min before euthanasia.
During this phase of the study the electrodes were positioned 2 cm
apart with an exposed electrode length of 2.5 cm. One animal was
treated with 3000 V/cm without reverse polarity and the remain-
ing three animals were treated with 2500 V/cm and repeat abla-
tion with reverse polarity as previously described. Animals were
then euthanized and the liver and pancreas were recovered for
analysis.
Results
All eight swine survived to the designated time. At the time
of laparotomy for euthanasia, one animal designated for 2-day
survival was noted to have a distended stomach consistent with
gastroparesis. This was felt to be more likely related to the laparo-
tomy than to the IRE directly. No other complications were
encountered.
Using two mono-polar electrodes as previously described, an
elliptical, dumbbell-shaped ablation zone was reliably created
(Fig. 1). Tissue within the zone of ablation exhibited features of
haemorrhagic necrosis (Fig. 2). Hepatocyte necrosis extended to
the margin of large hepatic veins within the zone of ablation
without evidence of heat sink (Fig. 1).
Ablation parameters and size are shown in Table 1. The ablation
zone for liver hilum ablations is larger and more irregular than for
intra-hepatic ablations using the same treatments parameters
(Table 1 + Fig. 3a). Large bile ducts, portal veins and hepatic arter-
ies within the portal triads appear more resistant to the effects of
IRE (Figs 2, 3b).
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TTC staining can predict the zone of ablation after IRE. The
surrounding, viable liver tissue retains the red dye. Tissue that is
not viable does not retain the dye, and therefore, does not stain
red. The ablation zone is predictable at 15 min after IRE using
TTC staining and becomes more apparent by 1 h (Fig. 4).
Two weeks after ablation by IRE, the liver is grossly and histo-
logically normal.
Mean total bilirubin was 0.1 mg/dL at baseline and on post-
ablation day 2. Mean total bilirubin peaked at 0.25 mg/dL on
post-ablation day 5 and normalized to 0.1 mg/dL by post-ablation
day 14. No identifiable pattern of change was noted for either
aspartate aminotransferase (AST) or alanine transaminase (ALT)
on post-ablation days 2, 5 and 14.
Discussion
Our results demonstrate for the first time that IRE can be per-
formed safely in the liver hilum for the ablation of liver tissue
around a major portal pedicle without collateral damage to the
bile duct, hepatic artery and portal vein and with no evidence of
incomplete ablation from heat sink. These findings suggest that
IRE may prove to be superior to conventional, thermal ablation
(e.g. RFA and MWA) for the treatment of small, unresectable liver
tumours abutting a major vascular or portal structure.
The estimated incidence of colorectal cancer was approximately
147 000 cases in the United States in 2009.
10
It is estimated that
40% of patients will develop liver metastasis at some time in their
disease course. Unfortunately, only about 10–25% of patients with
colorectal cancer metastatic to the liver will be candidates for liver
resection.
11–14
Hepatocellular carcinoma is one of the most common tumours
worldwide with an estimated incidence of 564 000 new cases in
2000.
15
Unfortunately, only about 10% of patients with hepatocel-
lular carcinoma are candidates for surgical resection at the time of
diagnosis.
16
Limitations in surgical treatment may be due either to the
extent of extra-hepatic disease, the extent of intra-hepatic disease
or limited functional hepatic reserve in the planned future liver
remnant. Liver tumour ablation has become a highly successful
tool in the treatment of unresectable liver tumours. Radiofre-
quency ablation has a 65% complete pathological response rate
for the treatment of small (<3 cm) hepatocellular carcinomas.
Results with microwave ablation appear similar.
1–3
As with all therapies, thermal ablation of liver tumours has
limitations. The first limitation for tumour ablation is tumour
size. When tumour size exceeds 3 cm the complete pathological
response rate falls to between 10 and 25%.
1,2
Recent data suggests
that microwave ablation may be more effective for tumours up to
4.5 cm; however, these data have not been corroborated in a pro-
spective trial with pathological correlation.
17
Figure 1 Liver irreversible electroporation (IRE) ablation using two
monopolar probes, spaced 2 cm apart with a 2-cm exposure. Abla-
tion was performed using 3000 V/cm and was repeated with reverse
polarity. The tissue was harvested 2 h after IRE ablation. (a) Shows
fresh tissue and (b) shows the tissue after fixation with triphenyltet-
razolium chloride. The area of necrosis extends to the wall of the
central vein (arrow) with preservation of the vein and no evidence of
heat sink
Figure 2 A20¥ photomicrograph depicts haemorrhagic necrosis of
the hepatocyte lobules after irreversible electroporation (IRE) abla-
tion. Portal structures are more preserved. Preserved bile ducts are
highlighted by the narrow arrows and the preserved portal vein is
highlighted by the wide arrow
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Table 1 Irreversible electroporation (IRE) ablations created with two monopolar probes positioned 2 cm apart in swine liver
Location n Exposure
a
Voltage (V/cm) Reverse polarity
b
Ablation zone (cm)
c
Intra-hepatic 9 2.5 cm 2500 yes 2.95 0.31 ¥ 1.5 0.44
Intra-hepatic 3 2.5 cm 3000 No 2.27 0.23 ¥ 1.5 0.2
Intra-hepatic 4 2 cm 3000 yes 3.25 0.35 ¥ 1.45 0.21
Liver hilum 4 2 cm 3000 yes 4.45 0.07 ¥ 1.8 0
a
Exposure refers to the length of the electrode that is active during delivery of the treatment.
b
Reverse polarity refers to repeating the IRE treatment without repositioning the electrodes but after reversing the polarity of the electrodes.
c
Width and height of the ablation zones were measured after triphenyltetrazolium chloride staining and fixation.
Figure 3 Liver irreversible electroporation (IRE) ablation with
monopolar electrodes positioned on either side of the portal triad,
2 cm apart in the liver hilum. Ablation was performed with
3000 V/cm and reverse polarity. The zone of ablation is larger and
more irregular when compared with intra-hepatic liver IRE ablations
(3a). Hepatocyte necrosis occurs immediately up to the fibrous
capsule of the portal triad with histological preservation of the
bile duct (BD), hepatic artery (HA) and portal vein (PV) (3b; 4¥
photomicrograph)
Figure 4 Triphenyltetrazolium chloride (TTC) staining can predict the
zone of ablation after irreversible electroporation (IRE). TTC fixed
liver tissue is shown 15 min (4a), 30 min (4b) and 1 h (4c) after IRE.
The surrounding, viable liver tissue retains the red, triphenyltetrazo-
lium chloride dye while dye washes out of the necrotic, ablated liver
over time. The ablation zone is predictable at 15 min and becomes
more apparent by 1 h. The zone of ablation is highlighted by the
dotted white line
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Thermal ablation by either microwave or radiofrequency is also
limited by collateral damage to surrounding structures. Liver
tumours abutting a major portal triad or central bile duct may not
be amenable to ablation for this reason.
Finally, heat sink refers to the loss of heat at the tissue level as a
result of adjacent circulating blood of a cooler temperature.
Tumours abutting a large hepatic vein or the inferior vena cava are
particularly vulnerable to local recurrence because of incomplete
ablation from heat sink.
Electroporation has been used in a reversible manner to
improve the delivery of bleomycin in the treatment of squamous
cell carcinoma of the head and neck.
18–22
IRE is a novel technique
of tissue ablation which utilizes short pulses of high frequency
electrical energy to kill cells via the creation of micropores in the
lipid bilayer of the cell membrane.
IRE has previously been shown to be an effective means of
ablating hepatocytes in swine liver with preservation of the portal
structures. IRE can induce hepatocyte necrosis immediately adja-
cent to large veins within the ablation zone, unaffected by heat
sink.
6,7
The experience using IRE to treat cancer remains limited. Miller
et al. reported the ability of IRE to ablate human hepatocarcinoma
cells in vitro. They showed that multiple pulses appeared to be
more effective in cancer cell ablation than delivery of the same
energy in a single pulse.
23
Al-Sekere et al. reported complete
regression in 12 of 13 cutaneous tumours implanted in mice using
IRE. Their work confirmed improved results with cancer cell
death using multiple short pulses of electrical energy.
24
We are the first to show that IRE is safe and effective for liver
tissue ablation in the liver hilum with a major portal pedicle
included within the zone of ablation. The bile duct, portal vein
and hepatic artery appear more resistant to the effects of IRE.
These findings suggest that IRE may prove to be superior to con-
ventional forms of thermal ablation for the treatment of small,
unresectable liver tumours abutting a major portal or vascular
structure. Additional studies will be needed to test this theory.
While the effects of thermal ablation are evident immediately
after treatment, the mechanism of cell death after irreversible
electroporation is a slower process. Gross inspection of liver tissue
immediately after IRE reveals oedema and haemorrhage; however,
the zone of ablation is not obvious either grossly or using H&E
staining.
TTC staining relies on the ability of viable cells to retain the dye
while non-viable cells do not. Fishbein et al. reported the ability of
triphenyltetrazolium chloride staining to reliably quantify myo-
cardial necrosis as early as 3 h after coronary artery occlusion
before histological changes are clearly diagnostic.
8
Our results show that TTC staining accurately predicts the zone
of IRE ablation as early as 15 min after IRE treatment. This is an
important advance that will open the door for future clinical trials
of IRE using an ablation followed by resection study design.
IRE requires the insertion of electrodes into the target tissue for
the delivery of the treatment. As with other forms of ablation (e.g.
radiofrequency ablation and microwave ablation), bleeding can
occur at the puncture site. The high voltage current needed for
ablation is unique to IRE. This necessitates reversible chemical
paralysis to prevent muscle contractions. Although cardiac
arrhythmias have been reported, the risk of arrhythmia may be
minimized with cardiac synchronization.
25
No IRE-related com-
plications were encountered in our study.
The only published report to date regarding treatment of
human tumours in vivo with IRE is from Ball et al. from Austra-
lia.
26
They reported primarily on the safety and complications
encountered while performing 28 IRE ablations in 21 patients.
Eight procedures treated renal tumours, 17 liver tumours and 3
lung tumours. In their experience, complications included tran-
sient systolic hypertension in all patients, muscular contractions
in inadequately paralyzed patients, post-operative pain after 13
procedures (46%), acid-base disturbances after 4 procedures
(14%) and pneumothorax related to electrode placement in three
procedures (11%). Of greatest significance, ventricular tachycar-
dia occurred during seven procedures (25%). In 4 of these 7 cases
the arrhythmia was associated with ‘markedly decreased blood
pressure. They report that all arrhythmias resolved immediately
after cessation of treatment. This study does not include any data
regarding tumour response or oncologic outcomes.
In conclusion, IRE appears to be safe and effective for ablation
of liver tissue in the liver hilum with preservation of the bile ducts,
hepatic arteries and portal veins within the zone of ablation.
Triphenyltetrazolium chloride staining accurately predicts the
zone of ablation as early as 15 min after treatment with IRE.
Conflict of interest
This study was partially funded by a grant from AngioDynamics, Inc.,
Queensbury, NY.
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    • "Since IRE is not temperature-dependent, it can be used on tumors adjacent to blood vessels. Importantly, IRE has been shown to effectively ablate tumors within the liver hilum while preserving the structure and functionality of the hepatic artery, portal vein, and bile duct [62,143,144]. There are no clinical trials yet comparing IRE to other ablation techniques; however, prospective studies suggest outcomes are similar [149]. "
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    • "Preliminary animal studies on the IRE ablation of perivascular porcine liver tissue have shown that this method is not affected by the common heat sink phenomenon [7, 12]. Complete tissue ablation up to the vessel wall could be achieved without any perivascular sparing, and vessels within the ablation zone remained patent at follow-up [6, 10, 12]. Similar results have been reported by Lee and colleagues after IRE ablation of VX2 tumors in rodent livers [13]. "
    [Show abstract] [Hide abstract] ABSTRACT: To evaluate risk factors associated with alterations in venous structures adjacent to an ablation zone after percutaneous irreversible electroporation (IRE) of hepatic malignancies at subacute follow-up (1 to 3 days after IRE) and to describe evolution of these alterations at mid-term follow-up.43 patients (men/women, 32/11; mean age, 60.3 years) were identified in whom venous structures were located within a perimeter of 1.0 cm of the ablation zone at subacute follow-up after IRE of 84 hepatic lesions (primary/secondary hepatic tumors, 31/53). These vessels were retrospectively evaluated by means of pre-interventional and post-interventional contrast-enhanced magnetic resonance imaging or computed tomography or both. Any vascular changes in flow, patency, and diameter were documented. Correlations between vascular change (yes/no) and characteristics of patients, lesions, and ablation procedures were assessed by generalized linear models.191 venous structures were located within a perimeter of 1.0 cm of the ablation zone: 55 (29%) were encased by the ablation zone, 78 (41%) abutted the ablation zone, and 58 (30%) were located between 0.1 and 1.0 cm from the border of the ablation zone. At subacute follow-up, vascular changes were found in 19 of the 191 vessels (9.9%), with partial portal vein thrombosis in 2, complete portal vein thrombosis in 3, and lumen narrowing in 14 of 19. At follow-up of patients with subacute vessel alterations (mean, 5.7 months; range, 0 to 14 months) thrombosis had resolved in 2 of 5 cases; vessel narrowing had completely resolved in 8 of 14 cases, and partly resolved in 1 of 14 cases. The encasement of a vessel by ablation zone (OR = 6.36, p
    Full-text · Article · Aug 2015
    • "Due to the many applications of the electroporation technique the development of the high power instrumentation applicable in this field is performed. Square wave electrical pulse systems are offering precise treatment intensity control due to the short rise and fall times and the pulse plateau region, and therefore are preferable in electroporation [23][25]. Due to the variety of the cell types and cell buffers used in biological sciences, the load of the electroporation system varies in a broad range (from several tens of up to several k). "
    [Show abstract] [Hide abstract] ABSTRACT: Subjection of biological cells to high intensity pulsed electric field results in the permeabilization of the cell membrane. Measurement of the electrical conductivity change allows an analysis of the dynamics of the process, determination of the permeabilization thresholds, and ion efflux influence. In this work a compact electro-permeabilization system for controlled treatment of biological cells is presented. The system is capable of delivering 5 μs – 5 ms repetitive square wave electric field pulses with amplitude up to 1 kV. Evaluation of the cell medium conductivity change is implemented in the setup, allowing indirect measurement of the ion concentration changes occurring due to the cell membrane permeabilization. The simulation model using SPICE and the experimental data of the proposed system are presented in this work. Experimental data with biological cells is also overviewed.
    Full-text · Article · Oct 2014
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