Scheingraber S, Richter S, Igna D, Girndt M, Flesch S, Kleinschmidt ...

Clin Transplant 2007: 21: 689–695 DOI: 10.1111/j.1399-0012.2007.00706.x
Copyright ª Blackwell Munksgaard 2007
Indocyanine green elimination but not
bilirubin indicates improvement of graft
function during MARS therapy
Scheingraber S, Richter S, Igna D, Girndt M, Flesch S, Kleinschmidt S,
Schilling MK. Indocyanine green elimination but not bilirubin indicates
improvement of graft function during MARS therapy.
Clin Transplant 2007: 21: 689–695. ª Blackwell Munksgaard, 2007
Abstract: Measurement of indocyanine green plasma disappearance rate
(PDR ICG ) has been suggested as a meaningful liver function parameter.
However, there are only very limited data concerning its value in the
monitoring of graft dysfunction (GDF) and primary non-function (PNF)
especially during molecular absorbent recirculating system (MARS) therapy.
This study was therefore performed to evaluate the diagnostic accuracy
to detect and monitor GDF with the measurement of the PDR ICG in direct
comparison with conventional markers like bilirubin and prothrombin time
(PT). Of the 19 liver recipients, four patients with GDF and two patients
with PNF were treated with 38 MARS cycles. Only PDR ICG did reliably
indicate liver function between patients with GDF/PNF and patients with
sufficient graft function who served as controls. Moreover, receiver operating
characteristic analysis showed the highest areas under the curve
(AUC) for PDR ICG (AUC PDRICG max : 0.840, AUC PDRICG max : 0.822), followed
by bilirubin (AUC bilirubin : 0.528) and PT (AUC PT : 0.546). In contrast
to the decrease of the serum bilirubin concentration due to MARS, a
noticeable improvement of PDR ICG was evident only in patients with GDF.
Patients with acute fulminant failure and PNF had significantly lower
PDR ICG values, which did not improve even during continuous MARS
treatments. Conclusively, monitoring of PDR ICG is superior to bilirubin
and PT measurements to determine the graft function especially in patients
with PNF and GDF undergoing MARS therapy.
Stefan Scheingraber a ,
Sven Richter a , Dorian Igna a ,
Matthias Girndt b , Sarah Flesch a ,
Stefan Kleinschmidt c and Martin
K. Schilling a
Departments of a General-, Visceral-, Vascularand
Pediatric Surgery, b Internal Medicine IV
(Nephrology) and c Anesthesiology and Intensive
Care Medicine, University Hospital, University of
the Saarland, Homburg, Germany
Key words: graft function – ICG clearance – liver
function – liver transplantation – MARS therapy –
reperfusion injury
Corresponding author: Dr. Stefan Scheingraber,
Department of General-, Visceral-, Vascular- and
Pediatric Surgery, University Hospital, University
of the Saarland, Homburg, Germany.
Tel.: +49 6841 1622502; fax: +49 6841 1631004;
e-mail: chstsc@uniklinik-saarland.de
Accepted for publication 14 March 2007
Orthotopic liver transplantation (OLTX) remains
the most important therapy for advanced liver
diseases and acute liver failure. However, due to
the discrepancy of the small number of grafts
available and multitude of patients on the waiting
list, the requirements on a graft to be suitable have
became scaled down. The organ shortage consequently
exerts a higher pressure to accept marginal
grafts with a higher percentage of primary nonfunctioning
(PNF) or graft dysfunction (GDF) in
the immediate period after OLTX. Early PNF or
severe GDF are the most common indications for
retransplantation-orthotopic liver transplantation
(Re-OLTX) within the first two wk postoperatively.
Therefore, careful monitoring of the graft function
and measures to prevent primary PNF are essential.
Furthermore, the molecular absorbent recirculating
system (MARS) has been proposed as a
therapeutical option for early GDF, but no clear
inclusion criteria or cut-off values of liver function
parameters have been defined so far (1). Because
conventional liver tests such as measurement of
bilirubin, transaminases activity, and blood coagulation
parameters are difficult to determine in the
early postoperative period, several authors have
attempted to evaluate the indocyanine green (ICG)
elimination capacity (2–4). ICG is excreted exclusively
by the liver, and invasive devices using pulse
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Scheingraber et al.
spectrophotometry became available for valid
bedside calculation of ICG plasma disappearance
rate (PDR ICG ) within 10 min (3, 5). It has been
reported that the diminished ICG elimination
reflects the degree of reperfusion injury and would
be a good marker of primary graft function (6). In
addition, ICG-clearance measurements showed a
significant correlation with the severity of preservation
injury, longer intensive care unit, and
hospital stay, prolonged liver dysfunction, and
septic complications (3). To further analyze the
diagnostic accuracy of the ICG-clearance monitoring
we (i) compared the PDR ICG with the
conventional markers bilirubin and prothrombin
time (PT) by calculation of receiver operating
characteristic curves (ROC) and (ii) evaluated the
possible superiority of PDR ICG measurements to
indicate the improvement of liver function during
MARS therapy in patients with PNF or GDF.
Methods
Patients and operative procedure
A total of 19 patients undergoing orthotopic liver
transplantation at the Department of General
Surgery, University Hospital of the Saarland
between June 2002 and April 2006 were entered
in this study. Cadaveric liver grafts were harvested
in cold UW-solution. After recipient hepatectomy,
ABO-identical grafts matched for ratio of physiological
body to liver weight were transplanted by
the standard technique with venovenous bypass in
16 and by the piggyback method in three cases. All
OLTX operations were performed by two surgeons
and the quality of reperfusion was estimated by the
responsible surgeon. Impaired reperfusion was
classified as prolonged discoloration of the grafts,
patchy perfusion defects during reperfusion, and
severe hepatic congestion. Reperfusion injury was
confirmed by evidence of structural injury in the
pre-and post-reperfusion liver biopsy.
Postoperative management
All patients received the same immunosuppressive
regimen consisting of steroids, azathioprin, and
continuous application of cyclosporin. Monitoring
of postoperative infections was performed by daily
determinations of procalcitonin, in addition to
routine parameters such as white blood cell count
and C-reactive protein as well as cultures of blood,
sputum, urine, peritoneal fluid, and bile fluid. The
diagnosis of rejection was made on the basis of
clinical, laboratory and histology findings, and
high-dose methylprednisone (1000 mg/d for three d)
was given whenever acute rejection was suspected.
Vascular complications were screened by frequent
Doppler ultrasonography, followed by angiography
whenever indicated. T-tube was placed routinely
and the bile concentration was determined in
the fluid sampled during 24 h. T-tube cholangiography
was performed in cases with suspected
biliary problems.
ICG measurement and laboratory data
Indocyaninine green plasma disappearance rate
was measured immediately after admission on the
surgical intensive care unit (SICU) and every
morning at 7.00 am during stay on the SICU.
Bilirubin and PT were determined on a daily
clinical routine basis in the laboratory of the
hospital using commercially available kits (Roche
Diagnostics, Mannheim, Germany). PDR ICG was
determined by means of a non-invasive monitor
(LIMON Ò , Pulsion Medical Systems, Munich,
Germany). A bolus of 0.25 mg/kg ICG was
administered via the central venous catheter and
the light absorption at two different wavelengths
(805 and 905 nm) was measured non-invasively by
a finger sensor for 10 min. After bolus administration,
ICG binds to plasma proteins remains in
the vascular compartment and is exclusively
metabolized by the liver without undergoing
enterohepatic circulation. Therefore, the PDR of
ICG equals ICG clearance by the liver and
depends on liver perfusion and hepatocellular
function. Normal PDR ICG values of 18–25%/min
with the Limon system were reported by the
manufacturer.
MARS treatment
Between July 2003 and April 2006, 38 MARS
cycles were performed in seven OLTX patients.
One MARS cycle lasted eight h. One patient with
fulminant liver failure (PT < 10%, encephalopathy
grade 3) after acute hepatitis B infection
received MARS for bridging to high urgent
(HU)-OLTX. The remaining six patients were
treated with MARS after OLTX, two patients
with primary graft non-function [PT < 10% with
continuous need for fresh frozen plasma (FFP),
PDR ICG < 5%/min] as bridging therapy for
HU-OLTX and four patients as support for
GDF. GDF was defined by increased bilirubin
serum concentrations >10 mg/dL or hepatic
encephalopathy grade 2 or more. PNF was
considered as a cause of graft failure only after
excluding rejection and vascular problems.
PDR ICG as well as bilirubin and PT were
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ICG clearance for graft function monitoring
measured before and after each MARS cycle. All
patients waiting for HU-OLTX required mechanical
ventilation, whereas all other patients were
breathing spontaneously. The decision to stop
MARS therapy in patients with GDF was based
on markers of liver function (hyperbilirubinemia
5%/min). Plasma coagulation
factors were not given when PT was below
40% (normal range 75–140%) unless the patient
was actively bleeding. During MARS dialysis
unfractioned heparin was given continuously
according to determinations of the activated
clotting time in 30–60 min intervals.
Statistics
All variables are presented as mean ± SEM. For
comparison of independent samples, ANOVA
and the Mann–Whitney U-test were used. ROC
curves and the respective AUC (7) were calculated
for the maximum value of bilirubin and
PDR ICG and the minimum value of PT and
PDR ICG during the SICU-stay. The best cut-off
was chosen as the value with optimal sensitivity,
specificity and likelihood ratio. Statistical calculations
were performed with the MedCalc Software
package (MedCalc Ò ; Mariakerke, Belgium)
(8). Values of p < 0.05 were considered significant.
Results
Patients’ characteristics
In Table 1, patientsÕ sex and age, underlying
etiology, hospital stay and graft, and overall
outcome are demonstrated. All but two patients
with multiple organ failure and sepsis survived.
There were four patients with GDF and two
patients with PNF in need for immediate
Re-OLTX. One patient with fulminant liver failure
caused by acute hepatitis B viral infection was
admitted with encephalopathy and severe coagulation
disorder and was listed for HU-OLTX. As
shown in Table 1, seven patients with GDF and
PNF received MARS-therapy. Mean SICU stay in
patients with GDF and PNF was 32 ± 19 d
(13–71 d) compared with 14 ± 8 d (4–34 d) in
patients with a good functioning graft.
Graft reperfusion
Three grafts showed macroscopically insufficient
reperfusion during OLTX with patchy ischemic
zones, incomplete wash out, and a swollen graft
after reperfusion. From these grafts, two (66%)
developed PNF with need for Re-OLTX. Four
other grafts showed moderate reperfusion in terms
of prolonged time of wash out or patchy ischemic
zones. From these, one (25%) graft was apparent
Table 1. Patients’ characteristics
Sex Age (yr) Etiology SICU-stay (d)
MARS cycles
(no. of cycles/days of treatment) Complication Outcome
M 50 Hep. C 14 – Rebleeding Well
F 56 Hep. B/D 13 – acRej, MOV Dead
M 53 Hep. C 71 5/23 MOV, GDF Dead
M 54 Hep. B/D, HCC 4 – None Well
F 53 Hep. C 5 – None Well
M 32 Hep. B, ALF 19 10/4 None (HU-OLTX) Well
M 51 Hep. C, HCC 6 – None Well
F 56 Hep. B/D 30 2/1 PNF [Re-OLTX] Well
M 55 alc. LC 18 – cand. pneu. Well
M 54 M. Wilson, HCC 11 – None Well
F 56 Hep. B 12 – RF Well
M 56 Hep. C, HCC 14 – None Well
M 39 PSC 6 – None Well
M 40 chron. GF 34 6/3 PNF [Re-OLTX] Well
M 44 PSC 16 – PVT, anast. leak Well
M 21 PBC 18 – PVT, acRej Well
M 64 Hemochr., HCC 31 4/7 GDF, RF Well
M 60 Hep. B 22 6/7 GDF, cholangitis Well
M 50 Hep. B/D 23 5/3 GDF Well
Hep., hepatitis; acRej, acute rejection; GDF, graft dysfunction; HCC, hepatocellular carcinoma; ALF, acute liver failure; PNF, primary non-function; HU-OLTX, high urgency
listed orthotopic liver transplantation; Re-OLTX, recurrent orthotopic liver transplantation; alc. LC, alcoholic liver cirrhosis; cand. pneu., candida pneumonia; RF, renal
failure (affording hemodialysis); PSC, primary sclerosing cholangitis; chron. GF, chronical graft failure; PVT, portal vein thrombosis; anast. leak., leakage of biliodigestive
anastomosis; PBC, primary biliary cirrhosis; hemochr., hemochromatosis.
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Scheingraber et al.
for GDF. Remaining 13 grafts showed homogeneous
reperfusion. However, three of these 13 (23%)
grafts developed GDF in the post-OLTX period.
Graft dysfunction
The differences in liver function markers between
patients without GDF compared with patients with
GDF were analyzed for the first seven d after
OLTX (Table 2). During the first three d after
OLTX, PDR ICG values were significantly higher in
the group with sufficient graft function (controls)
compared with graft, which presented with PNF or
developed GDF. Seven d after OLTX the initially
low-PDR ICG values increased markedly in the
PNF/GDF group. In contrast, bilirubin levels were
not significant between both study groups at the
three examined time points nor did show any
significant decrease in during the first week. Paradoxically,
PT values remained significantly lower in
the control group compared with the PNF/GDF
group throughout all examined time points. Moreover,
PT values did significantly increase in the
PNF/GDF group. There were three patients in the
control group with need of FFP (11 U for two
patients, and 4 U for another patient) due to
bleeding problems or marked consumption of
coagulation factors. However, in all these patients
with low PT values and need for FFP there were no
indices for liver dysfunction and the patients course
was well. Interestingly, despite low PT levels (44%,
48%, 55%) the PDR ICG values were only slightly
decreased (13.1%/min, 16.2%/min, 16.5%/min).
As PNF and GDF developed at different time
points, ROC analysis was calculated for the lowest
as well the highest PDR ICG value, the highest
bilirubin value and the lowest PT value during the
first seven d after OLTX (Fig. 1A-D). The AUCs
considering sensitivity as well as specifity showed
significant differences between these three markers
regarding the diagnosis of postoperative GDF. The
highest AUC was found for the highest PDR ICG
value (AUC PDRICG max : 0.840) followed by the
lowest PDR ICG (AUC PDRICG min : 0.822), the AUC
values for bilirubin (AUC bilirubin : 0.528) and for PT
(AUC PT : 0.546). The differences between the AUC
for the highest PDR ICG value and the AUC for
bilirubin or PT were statistically significant (AUC bilirubin
vs. AUCICGmax: p = 0.005; AUC PT vs. AUC
ICGmax: p = 0.002). The optimal PDR ICG cut-off
level with the highest sensitivity and specificity in
the diagnosis of GDF was 10 mg/dL we did not observe a PDR ICG value
>12%/min. On the other hand, at very high
bilirubin levels >25 mg/dL, there were no very
low-PDR ICG values (

A 100
80
Sensitivity
60
40
20
0
B 100
80
Sensitivity
60
40
20
0
C 100
80
Sensitivity
60
40
20
0 20 40 60 80 100
100-Specificity
0 20 40 60 80 100
100-Specificity
ICG clearance for graft function monitoring
the dialysis filters. Patients with GDF received in
median five cycles on 10 d, comprising 28% of the
day, thus one cycle followed by a therapy break of
16 h. MARS treatment caused a significant decrease
of the serum bilirubin concentration from
14.1 ± 1.3 mg/dL before to 10.7 ± 0.7 mg/dL
(p < 0.05) after MARS therapy. The amount of
the bilirubin decrease was correlated with the peak
value of the serum bilirubin (r = 0.90, p < 0.05).
In contrast to the decrease of the serum bilirubin
concentration due to MARS, a noticeable improvement
of PDR ICG was evident only in patients
with GDF but not in patients with bridging
therapy (Fig. 2). Patients with acute fulminant
failure and PNF had significantly lower PDR ICG
values, which did not improve even during continuous
MARS treatments. Accordingly, there was
no need for FFP in patients with GDF, whereas
patients undergoing bridging therapy received
3.6 ± 1.3 U (0–15 U) FFP. The PT values were
significantly higher in the group with GDF
(84.1 ± 2.4% vs. 37.2 ± 3.1%; p < 0.05). In
patients with GDF there was no change in the
PT values after MARS cycles compared to baseline
levels before MARS (88.7 ± 2.6% vs. 84.4 ±
2.5%; p = 0.10). In all patients after OLTX a
T-tube was placed intraoperatively in the common
hepatic bile duct. However, only in patients with
GDF bile was produced and therefore only in this
group the bilirubin concentrations could be analyzed
before and after MARS treatment. We did
not observe any change in the bilirubin concentration
in the bile after any MARS cycles indicating
0
D 100
80
0 20 40 60 80 100
100-Specificity
20.0
17.5
15.0
12.5
10.0
Bilirubin (mg/dL)
PDR ICG (%/min)
#
#
#
Sensitivity
60
40
20
0
0 20 40 60 80 100
100-Specificity
Fig. 1. Receiver operating characteristic curves of the most
pathological post-orthotopic liver transplantation bilirubin
(A), PT (B) the lowest (C) and the highest (D) plasma disappearance
rate (PDR ICG ) values regarding the occurrence of
graft dysfunction.
7.5
5.0
2.5
0.0
Before MARS After MARS Before MARS After MARS
Graft dysfunction
20 cycles in four patients
*
Bridging in non-function
18 cycles in three patients
Fig. 2. Serum bilirubin concentrations and plasma disappearance
rate (PDR ICG ) measured before and after molecular
absorbent recirculating system (MARS) cycles in the group of
patients with graft dysfunction (GDF) and the other group
with graft non-function. Mean ± SEM; * p < 0.05 vs.
patients with GDF, Mann–Whitney U-test;
# p < 0.05 vs.
baseline values, Mann–Whitney U-test.
693

Scheingraber et al.
that the hepatic bilirubin excretion did not
improve.
Discussion
Indocyanine green is a synthetic dye that is
eliminated by the liver without extrahepatic metabolism
and excretion; therefore, its blood clearance
depends on the plasma volume, hepatic perfusion,
and the hepatocellular excretion rate. The PDR ICG
has been applied to determine the liver donor
function in liver transplantation. In an animal
study, the PDR ICG decreased significantly after
OLTX and correlated well with hypotensive episodes
and ischemic time during the donor operation
(2). In a clinical study, the PDR ICG measured
just before procurement showed a good correlation
with donor age and with the histologic score of
liver damage (4). In addition, in this study, the
PDR ICG had no relation to PT and transaminases.
Comparing the PDR ICG measured just before
procurement, the postoperative PDR ICG was significantly
higher in accepted compared with discarded
grafts (9). However, two grafts which were
accepted had a PDR ICG < 15%/min and developed
PNF.
The PDR ICG and the clearance of ICG, which
corresponds to the product of the PDR ICG and the
volume of distribution of the dye, were measured
in nine patients undergoing OLTX (10). The
PDR ICG was at pathological low values before
OLTX and diminished further during the anhepatic
phase. Immediately after reperfusion the PDR ICG
increased to almost normal values and showed a
slight decrease 24 h after OLTX. However, the
PDR ICG 24 h after OLTX was markedly higher
than baseline levels before OLTX. As the plasma
volume was increased at baseline and remained
increased during surgery, the PDR ICG values tended
to be relatively lower than the ICG-clearance values.
However, the perioperative pattern and time course
of the PDR ICG was very similar to that of the ICG
clearance and thus the authors concluded that it
seems justified to use the PDR ICG , which is
independent of the amount of ICG administered.
Another topic was the technique of how the PDR ICG
should be measured, as a non-invasive finger probe
has become available for routine clinical monitoring.
It has been shown in several studies that the
non-invasive transcutaneous pulse-densitometric
method correlates well with the invasive aortic
fiber-optic or with the conventional invasive ICG
clearance test with the spectophotometric analyses
of multiple blood samples (3, 11–13).
In addition to the methodological considerations
concerning the measurement of the PDR ICG , some
studies focused on the role of PDR ICG as a test of
graft function in the early post-OLTX period. In a
multivariate analysis of the PDR ICG and other liver
function tests with regard to the clinical outcome
after 50 OLTX, a low-PDR ICG especially on POD 1
after OLTX was closely correlated with the severity
of preservation injury prolonged liver dysfunction,
septic complications, a longer SICU and hospital
stay (3). The finding that a low-PDR ICG reflects
perfusion injury and that the PDR ICG measured
24 h after OLTX is therefore an early predictor of
graft function was also confirmed by another group
(6). However, no study so far has reported a precise
characterization of the diagnostic accuracy of
PDR ICG as well as bilirubin and PT by calculating
ROC curves. In this study, all three examined
markers were significantly different between grafts
with sufficient function and grafts with dysfunction.
However, by calculating the AUC in ROC curves,
we found the highest AUC for PDR ICG to detect
GDF. Although levels >10 mg/dL of bilirubin
were used to define GDF, and therefore bilirubin
was part of the outcome criteria for the ROC
analysis, the AUC for bilirubin was lower compared
with the AUC of PDR ICG . The disadvantage
of bilirubin might be its relatively long half-life. The
relatively low AUC of PT can be explained by the
fact that it is largely affected by bleeding episodes as
well as the administration of FFPs. Especially in
the initial phase, immediately after OLTX, we
found in this study that interpretations of PT values
can be very misleading and low-PT values can be
associated with relatively normal PDR ICG values.
Thus, the major advantage of PDR ICG compared
with bilirubin and PT is that this marker shows
marked differences even at the range of normal
bilirubin and PT values.
In this study, PNF and GDF were treated with
MARS therapy. As there was no increase in the
low-PDR ICG of the non-function group the efficacy
of MARS in fulminant liver failure besides detoxification
remains questionable. In contrast, the
significant improvement in the PDR ICG of patients
with GDF group favors our concept of MARS in
post-OLTX GDF. Nevertheless, in this group,
MARS could not improve bilirubin excretion as no
significant changes of the bilirubin concentrations
were detected in the collected bile. As the serum
bilirubin concentration is lowered by the MARS
treatment itself, the PDR ICG is obviously a better
marker for monitoring of liver function during
MARS therapy.
As ICG is an organic anion like bilirubin, its
hepatic uptake at the basolateral membrane of the
hepatocyte is probably mediated by the same
transport proteins (14). Therefore, lowering the
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ICG clearance for graft function monitoring
serum bilirubin concentration due to MARS can
increase the number of binding sites of the
hepatocellular uptake. However, as this process is
ATP-dependent (15), extensively damaged livers
are unable for ICG-uptake resulting in a low
PDR ICG . Conclusively, monitoring of PDR ICG is
superior than bilirubin and PT measurements to
determine the graft function especially in patients
with PNF and GDF undergoing MARS therapy.
Acknowledgement
The authors wish to thank Bettina Rau, MD (Department
General Surgery, University Hospital of the Saarland) for
her assistance in calculation the ROC.
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