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Fluids administration and coagulation characteristics in patients with different model for end-stage liver disease scores undergoing orthotopic liver transplantation

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Fluids administration and coagulation characteristics in patients with different model for end-stage liver disease scores undergoing orthotopic liver transplantation

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There have been many studies investigating the impact of the model for end-stage liver disease (MELD) score on predicting post-transplant outcome. But it is unclear whether MELD is correlated to intraoperative fluid therapy and coagulation status. We investigated the relationship between the severity of liver diseases as measured by MELD score and intraoperative fluid requirements and the changes of coagulation characteristics. Ninety patients were included in this retrospective study. The patients were stratified into three groups according to the MELD scores: < 15 (low), 15 - 25 (medium) and > 25 (high). Intraoperatively, volume was restored with allogeneic and/or salvaged red blood cells (RBC), fresh-frozen plasma (FFP), platelet and other types of fluids according to hemodynamic data, hematocrit, and clotting data. Intraoperative coagulation data, blood requirements and other fluids administered were compared among the 3 groups. Before surgery, in addition to the three variables used to calculate MELD scores in other baseline laboratory values, including ratio of activated partial thromboplastin time (R-APTT), D-Dimer, hematocrit, platelet and blood urea nitrogen (BUN) were significantly different among the 3 groups. The blood loss increased with increasing MELD. The volume of RBC (allogeneinc, salvaged and total), FFP, platelet and the total volume of transfusion were also significantly different among the three groups (P < 0.01). The requirements for prothrombin complex and fibrinogen showed a similar pattern. During operation, the changing trends of each coagulation variable were different. Compared with baseline, during each intraoperative stage, INR and R-APPT increased in the low MELD group. While in the medium MELD and high MELD groups, INR did not changed significantly during the operation, and R-APPT significantly increased only after reperfusion. This study provided some useful information for perioperative management of patients undergoing liver transplantation. Careful preoperative planning and resource preparation are crucial for patients with high MELD scores. Close communication between surgeon, anesthesiologist and the transfusion staff of blood bank before and during surgery should be stressed.
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Chinese Medical Journal 2007; 120(22):1963-1968
1963
Original article
Fluids administration and coagulation characteristics in
patients with different model for end-stage liver disease
scores undergoing orthotopic liver transplantation
LI Min, ZHANG Li-ping and YANG Lu
Keywords: liver transplantation; fluid therapy; coagulation, blood
Background There have been many studies investigating the impact of the model for end-stage liver disease (MELD)
score on predicting post-transplant outcome. But it is unclear whether MELD is correlated to intraoperative fluid therapy
and coagulation status. We investigated the relationship between the severity of liver diseases as measured by MELD
score and intraoperative fluid requirements and the changes of coagulation characteristics.
Methods Ninety patients were included in this retrospective study. The patients were stratified into three groups
according to the MELD scores: <15 (low), 15–25 (medium) and >25 (high). Intraoperatively, volume was restored with
allogeneic and/or salvaged red blood cells (RBC), fresh-frozen plasma (FFP), platelet and other types of fluids according
to hemodynamic data, hematocrit, and clotting data. Intraoperative coagulation data, blood requirements and other fluids
administered were compared among the 3 groups.
Results Before surgery, in addition to the three variables used to calculate MELD scores in other baseline laboratory
values, including ratio of activated partial thromboplastin time (R-APTT), D-Dimer, hematocrit, platelet and blood urea
nitrogen (BUN) were significantly different among the 3 groups. The blood loss increased with increasing MELD. The
volume of RBC (allogeneinc, salvaged and total), FFP, platelet and the total volume of transfusion were also significantly
different among the three groups (P<0.01). The requirements for prothrombin complex and fibrinogen showed a similar
pattern. During operation, the changing trends of each coagulation variable were different. Compared with baseline,
during each intraoperative stage, INR and R-APPT increased in the low MELD group. While in the medium MELD and
high MELD groups, INR did not changed significantly during the operation, and R-APPT significantly increased only after
reperfusion.
Conclusions This study provided some useful information for perioperative management of patients undergoing liver
transplantation. Careful preoperative planning and resource preparation are crucial for patients with high MELD scores.
Close communication between surgeon, anesthesiologist and the transfusion staff of blood bank before and during
surgery should be stressed.
Chin Med J 2007;120(22):1963-1968
he model for end-stage liver disease (MELD) was
implemented on 2002 by the United Network for
Organ Sharing (UNOS) as a tool for allocating organ in
liver transplantation. It can be used to estimate the
severity of liver disease and mortality of the patients on
the waiting list.
1
In comparison with the ChildTurcotte
Pugh score, the MELD score offers certain advantage by
excluding subjective variables and using only objective
laboratory parameters which includes serum creatinine,
total serum bilirubin (T-Bil) and the international
normalized ratio (INR) of the prothrombin time (PT).
2
There have been many studies concerning the MELD
scores impact on the mortality of those awaiting for
orthotopic liver transplantation (OLT) and the short and
long term mortality of those after OLT.
3-8
But there are
relatively few studies which analyzed the association of
MELD scores with intraoperative management of OLT.
The current study focused on the relationship between the
severity of liver diseases as measured by MELD score
and intraoperative fluid requirements and the changes of
coagulation characteristics.
METHODS
Patients
From January 1, 2003 to June 31, 2006, ninety-two adult
patients underwent OLT at Peking University Third
Hospital. After the approval of the institutional review
board, records of all the recipients were reviewed.
Patients undergoing retransplantation were excluded from
the study.
Anesthesia and monitoring
Anesthetic management was similar in all patients.
Anesthesia was induced by midazolam 0.05–0.10 mg/kg,
propofol 1.5–2.5 mg/kg, fentanyl 3–5 µg/kg and
vecuronium 0.1 mg/kg. Anesthesia was maintained with
T
Department of Anesthesiology, Peking University Third Hospital,
Beijing 100083, China (Li M, Zhang LP and Yang L)
Correspondence to: Dr. ZHANG Li-ping, Department o
f
Anesthesiology, Peking University Third Hospital, Beijing 100083,
China (Tel: 86-10-62017691. Email: lipingzhang01@yahoo.com. cn)
This study was supported by a grant from the Capital Medical
Development Foundation (No. 2003-1016).
Chin Med J 2007;120(22):1963-1968
1964
inhalation of isoflurane, infusion of propofol and
intermittent injection of fentanyl. To provide optimal
surgical conditions pipecurium was given as needed.
Anesthesia monitoring included ECG, intra-arterial, central
venous and pulmonary arterial pressure monitoring, pulse
oxymetry, capnography, urine output and blood
temperature. Dopamine, phenylephrine, norepinephrine, or
epinephrine was used as needed to maintain hemodynamic
stability. Calcium chloride was administered to maintain
serum calcium concentrations between 2.0–2.3 mmol/L,
patients were kept warm using forcing-air heating blanket,
warm mattress and intravenous fluids were administered
through a fluid warmer.
Blood transfusion and fluid replacement
Colloids and crystalloids were administered by the
guidance of clinical condition (e.g. fasting time, duration
of surgery, acuity of blood loss, changes in hemodynamic
status and unrine output). Intraoperative salvage of blood
was used in the absence of cancer. Packed red blood cells
and/or salvaged red blood cells were transfused to
maintain haematocrit above 25%. INR greater than 1.5
was the index for administration of fresh frozen plasma
(FFP). Prothrombin complex was also considered when
the INR was high. Platelet was given when the platelet
count fell below 50×10
9
/L. Fibrinogen was administered
to maintain fibrinogen levels above 1 g/L.
Blood analysis and data collection
Blood samples were taken before anesthesia induction
(T1), 2 hours after beginning of surgery, i.e. during
dissection (T2), during the anhepatic phase (T3), 10
minutes after reperfusion of the graft (T4), at the end of
the surgical procedure (T5).
All patients records were reviewed, and the following
data were collected: demographic characteristics; etiology
of liver disease; duration of surgery; anhepatic time; the
number of cases aided by veno-venous bypass;
intraoperative blood loss; urine output, fluid and blood
product requirements; perioperative analysis of INR, ratio
of activated partial thromboplastin time (R-APTT),
D-Dimer, fibrinogen, platelet count and hematocrit (Hct)
and preoperative creatinine, T-Bil, albumin, blood urea
nitrogen (BUN), alanine aminotransferase (ALT), alkaline
phosphatase (ALP) and potassium (K
+
).
MELD score was calculated for each patient using the
immediate preoperative data according to the formula:
MELD score = 9.57×log
e
creatinine (mg/dl) + 3.78×log
e
bilirubin (mg/dl) + 11.20×log
e
INR + 6.43 (available at:
http://www.unos.org/resources). Scores exceeding 40 by
calculation from the MELD formula were capped to 40.
The patients were stratified into three groups according to
the pretransplant MELD score: <15 (the low MELD
group, LG), 15–25 (the medium MELD group, MG) and
>25 (the high MELD group, HG) as demonstrated in
Onaca’s
9
and Naglers study.
10
Statistical analysis
The statistical program used in this study was SPSS 11.0
for Windows (SPSS Inc., Chicago, IL, USA). For
descriptive analyses, continuous variables were expressed
as numbers or mean ± standard deviation (SD) and
categorical variables as numbers of cases or proportions.
For continuous data, overall differences were tested by
ANOVA or Kruskal-Wallis test. For categorical data,
significance of differences was determined by chi-square
test. The difference was regarded as statistically
significant when the P<0.05. For intraoperative
coagulation data, repeated measures of general liner
model was used to determine the effects of time and
group respectively. P<0.05 was considered statistically
significant. In the same group, each parameter at different
intraoperative time was compared with each other by
Bonferroni test with significant level at 0.05.
RESULTS
Demographic and surgical data
From January 1, 2003 to June 31, 2006, ninety-two
patients received OLT in our hospital. Two patients
undergoing retranplantation were excluded from this
study. Demographic and pretransplant laboratory data of
the 90 patients are shown in Table 1. There were no
differences among groups with age, weight and gender
distribution. The age distribution ranged from 26 to 78,
with majority of male (90%). The main preoperative
diagnoses were cirrhosis and hepatocarcinoma. The
distributions of diagnosis were different in different
groups. The percentage of patients with cirrhosis was
31.4%, 52.8% and 61.2% in the low, medium and high
MELD group respectively; whereas the percentage of
patients with hepatocarcinoma was 68.6%, 41.7% and
10.5% in the low, medium and high MELD group
respectively.
The mean pretransplant MELD score of all patients was
17.70±8.36 and the range was 3.59–40.00. The mean
MELD score for LG was 9.87±3.05 (n=35), for MG
18.91±3.41 (n=36) and for HG 29.86±5.21 (n=19). There
were no significant differences among the three groups
with respect to anhepatic duration, surgery duration and
the number of surgery aided by veno-venous bypass
(Table 1) .
Pretransplant laboratory test
The three variables used to calculate MELD scores,
including INR, creatinine and bilirubin, were significantly
different among the 3 groups. Other baseline laboratory
values, including R-APTT, D-Dimer, platelet count, HCT
and BUN were also significantly different. There were no
significant differences in preoperative ALT, ALP, albumin,
calcium and K
+
(Table 2).
Intraoperative input and output
The input and output during the surgery are shown in
Table 3. There were significant differences of blood loss
Chinese Medical Journal 2007; 120(22):1963-1968
1965
Table 1. Demographic and surgical data
Characteristics Overall (n=90) LG (n=35) MG (n=36) HG (n=19) P values
Age (y) 48±10 49±10 46±9 48±12 0.235
Gender (Male/Female) 80/10 30/5 33/3 17/2 0.724
Weight (kg) 69±12 69±12 68±11 70±14 0.760
Diagnose (n)
Cirrhosis/Hepatocarcinoma/Others
42/41/7
11/24/0
19/15/2
12/2/5
0.000
**
MELD score 17.70±8.36 9.87±3.05 18.91±3.41 29.86±5.21
Duration of surgery (h) 9.6±1.4 9.5±1.5 9.6±1.2 9.7±1.5 0.946
Duration of anphepatic (min) 91±28 89±28 91±27 94±32 0.818
Veno-venous bypass (n/N) 17/90 7/35 5/36 5/19 0.522
**
P<0.01, compared among the 3 groups. LG: low MELD group; MG: medium MELD group; HG: high MELD group.
Table 2. Pretransplant laboratory data
Index Overall (n=90) LG (n=35) MG (n=36) HG (n=19) P values
T-Bil (μmol/L) 109.3±135.3 25.3±14.8 113.0±109.0 257.2±173.4 0.000**
ALT (U/L) 65±119 54±31 49±25 116±252 0.891
ALP (U/L) 121±64 129±74 122±64 103±34 0.755
Albumin (g/L) 34±10 35±14 33±6 34±5 0.767
Creatinine (μmol/L) 82±36 75±20 71±19 116±60 0.001**
BUN (mmol/L) 5.7±4.0 4.4±2.0 5.5±3.1 8.6±6.3 0.007**
Calcium (mmol/L) 2.14±0.36 2.16±0.41 2.11±0.26 2.17±0.42 0.834
INR 1.94±0.81 1.32±0.24 2.05±0.60 2.89±0.82 0.000**
R-APTT 2.00±1.41 1.33±0.41 2.09±1.46 3.08±1.79 0.000**
D-Dimer (μg/ml) 0.60±0.66 0.37±0.32 0.59±0.56 1.05±1.01 0.047*
Fibrinogen (mg/dl) 223±122 315±140 175±60 145±52 0.000**
Platelet (¯10
9
/L) 92±71 108±62 82±80 86±59 0.016**
Hct (%) 29.6±7.2 32.6±8.2 28.2±5.4 26.6±6.8 0.003**
K
+
(mmol/L) 3.95±0.49 3.94±0.57 3.94±0.50 3.97±0.29 0.763
*
P<0.05,
**
P<0.01, compared among the 3 groups. LG: low MELD group; MG: medium MELD group; HG: high MELD group.
Table 3. Intraoperative input and output
Index LG (n=35) MG (n=36) HG (n=19) P values
Blood loss (ml) 3844±4045 6732±5184 7122±6535 0.002**
Urine Output (ml) 2236±771 1871±782 1413±1023 0.005**
Allogeneic RBC (ml) 1973±2146 2997±2253 4158±3355 0.001**
Salvaged RBC (ml) 242±448 884±1235 1917±2218 0.000**
Total RBC (ml) 2215±2162 3842±2749 6075±4840 0.000**
FFP (ml) 2240±1756 3979±2404 4894±3337 0.000**
Platelet (ml) 43±129 217±274 239±293 0.003**
Total transfusion (ml) 4498±3867 8037±4962 11207±7634 0.000**
Crystalloid (ml) 5263±1274 5279±2022 5069±1603 0.515
Colloid (ml) 1371±634 1111±465 1158±443 0.130
Fibrinogen (g) 1.4±1.8 2.7±2.0 4.2±3.1 0.000**
Prothrombin complex (PE) 163±380 992±1131 1421±1536 0.000**
**
P<0.01, compared among the 3 groups. LG: low MELD group; MG: medium MELD group; HG: high MELD group.
and urine output among the three groups (P<0.01). The
blood loss increased with increasing MELD, while the
urine output decreased. The volume of RBC (allogeneinc,
salvaged and total), FFP, platelet and the total volume of
transfusion were also significantly different among the
three groups (P<0.01). The requirements for prothrombin
complex and fibrinogen showed a similar pattern. The
administration of crystalloid and colloid were not
different among the three groups.
Perioperative coagulation test
Over the course of the study, all the three coagulation
variables INR of PT, R of APTT and D-Dimer changed
from time to time (P<0.01) (Table 4). And there were
considerable variations in INR, R and D-Dimer among
different groups (P<0.001). But the changes of each
coagulation variables were not the same. Compared with
baseline, during each intraoperative stage, INR and
R-APPT increased in LG. While in MG and HG, INR
did not change significantly during the operation, and
R-APPT significantly increased only after reperfusion.
The changing trend of D-Dimer showed a similar patter
in the three groups, which was significantly increased
after reperfusion (P<0.05).
DISCUSSION
MELD score is an objective measurement of the severity
of the liver diseases which is not influenced by subjective
assessment. It was illustrated in our study that, besides of
INR, most of the other preoperative coagulation
parameters were deteriorated in higher MELD groups. As
we know, PT measures the extrinsic pathway and APTT
measures the intrinsic pathway of coagulation.
11
In
patients with worsened liver damage, the synthesis of
both extrinsic pathway factors and intrinsic pathway
factors are depressed.
12
The preoperative PT and APTT
data in this study were in accordance with the fact that the
Chin Med J 2007;120(22):1963-1968
1966
Table 4. Perioperative coagulation data
T1 T2 T3 T4 T5 P values
INR (PT) (sec)
LG 1.32±0.24 1.68±0.40
*
1.76±0.40
*
2.12±0.76
*
2.07±0.62
*
MG 2.05±0.60 1.95±0.60 2.04±0.76 2.26±0.83 2.14±0.61
HG 2.89±0.82 2.55±0.83 2.46±0.78 2.70±1.05 2.53±0.97
0.000
R (APTT) (Sec)
LG 1.33±0.41 1.94±0.89
*
2.22±1.17
*
3.07±1.35
*
2.81±1.44
*
MG 2.06±1.31 2.18±0.71 2.56±1.20 3.15±1.43
*
3.08±1.49
*
HG 2.72±1.55 2.79±1.59 3.07±1.70 3.91±1.85
*
3.60±1.82
*
0.002
D-Dimer (μg/ml)
LG 0.37±0.32 0.53±0.57 0.62±0.67
*
0.83±0.64
*
1.10±0.66
*
MG 0.59±0.56 0.86±0.83 0.97±1.07 1.22±1.02
*
1.78±1.41
*
HG 1.05±1.01 1.35±1.41 1.75±1.60 2.15±1.64
*
2.47±1.77
*
0.000
*
The mean difference was significant at 0.05 level compared with T1. LG: low MELD group; MG: medium MELD group; HG: high MELD group.
degree of impairment of clotting factors as an expression
of decreased liver synthesis was related to the severity of
liver damage. The decreased plasma fibrinogen and
elevated levels of D-Dimer in higher MELD groups
demonstrated in present study also supported the theory
that increased fibrinolysis was more common in patients
with advanced liver disease.
13
Some other preoperative laboratory data such as BUN,
platelet and Hct were also different among the groups.
The overall abnormality in coagulation, hepatic and renal
function in medium and high MELD patients might be
regarded as an alarm to the surgeon and the
anesthesiologist that these groups of patients need special
care. But in present study, there were no significant
differences among the three groups with respect to
anhepatic phase duration, total surgery duration and the
needs of veno-venous bypass. It might indicate that the
MELD score may not have close relationship with the
complexity of the surgical procedure.
Would MELD score have some sort of connection with
the ease or the difficulty of anesthesia management
during intraoperative period and resource consumption?
There are a number of reports that have analyzed
preoperative clinical and laboratory variables in relation
to intraoperative transfusion requirements.
14-19
Some
studies have indicated that several preoperative variables,
including coagulation abnormalities,
15,18
the levels of
creatinine, and bilirubin,
17
were associated with
intraoperative transfusion requirements. Since MELD is
calculated on the base of INR, creatinine and bilirubin, it
would not be surprising, if MELD would have an
influence on intraoperative fluid management as
illustrated in present study.
Brown et al
2
reported that there was a trend toward to
greater transfusion requirements with increasing MELD
score, although the P value was not statistically
significant. In another study, univariate analysis
demonstrated MELD score influenced the RBC
transfusion rate.
20
However when patients were divided
into two groups according to transfusion volume, MELD
score lost their predictive strength. Recently, Frasco et
al
21
detected a significant association between MELD and
total number of transfusions (in living donation OLT and
cadaveric donation OLT as a whole population). MELD
score was the factor that most strongly associated with
the number of transfusions. On average, an increase of 3
points in MELD score was associated with one additional
blood component treatment.
Our results were consisted with the study made by Xia.
22
But the mean MELD score was 27.86± 9.07 in their study
which was much higher than ours. A cutoff point of
MELD 30 was chosen in their study, and the patients
were divided into 2 groups: a low MELD group with
scores of 30 or lower and a high MELD group with
scores greater than 30. Their results suggested that
intraoperative transfusion requirements (RBC, FFP,
platelets and cryoprecipitate) and use of vasopressors
were significantly increased in patients with high MELD
scores compared to patients with low MELD scores.
Replacement therapy criteria for OLT varied in different
centers, but the aim of replacement therapy was similar
which emphasis the restoration of haemostasis. Although
our criteria was set according to introperative hamostatic
analysis, actually during the operation, decisions about
replacement therapy also incorporated clinical factors.
These included the presence or absence of generalized
oozing and clot formation in the surgical field, and the
likelihood of further surgical hemorrhage. Different from
other studies,
2,21,22
cryoprecipitate was not used in present
study because it was unavailable in our practice. FFP,
prothrombin complex, FIB and platelet were used to
compensate imbalances in the coagulation system in this
study. The consumptions of all the materials mentioned
above were significantly higher in medium and high
MELD group than in low MELD group (Table 3). The
result was in accordance with the fact that patients in
medium and high MELD groups had more serious
damage and necrosis of liver, more severe clotting factor
deficiencies.
Although there were numbers of studies investigating the
changes of haemostatic variables during OLT,
23-25
up to
now there was no research analyzing the relationship of
Chinese Medical Journal 2007; 120(22):1963-1968
1967
MELD and the haemostatic variables at different stages
of OLT. It was shown in our study that the changing
trends of various variables were not the same.
During operation, INR increased significantly compared
with baseline in LG, while INR did not changed
significantly in MG and HG. This result may reflect the
effect of the replacement therapy. The percentage of
patient whose baseline INR was greater than 1.5 was 26%
in LG, 86% in MG and 95% in HG. Based on our infusion
protocol, for the majority of patients in MG and HG, the
infusion of FFP and/or prothrombine complex started
soon after the beginning of surgery to correct clotting
factor deficiencies. While for most of patients in LG, the
infusion of FFP and prothrombine complex was not so
radical. So the hemostastic variables deteriorated in LG
due to blood loss and dilution of the clotting factors.
While INR in MG and HG kept stable owing to active
replacement therapy. Actually, during dissection and
anhepatic phase, INR in HG even showed a little
improvement, although the different was not statistically
significant. A recent research showed that the most
important variable determining the amount of change in
the INR with FFP transfusion was the pretransfusion
INR.
26
It indicated that the higher the pretransfusion INR,
the greater improvement of INR observed after FFP
transfusion.
Although in the medium and high MELD groups, the
changes of INR were not significant during operation,
R-APPT significantly increased after reperfusion. This
was in accordance with the fact that APTT was more
sensitive to heparin. After reperfusion, there is a great
amount of heparin like substances released from the
graft.
27
This could explain why APTT prolonged in all of
the three groups after reperfusion.
The results of present study might provide some useful
information for perioperative management of patients
undergoing liver transplantation. For patients with high
MELD score, consumption of blood product may be
higher. Before surgery, careful planning and resource
preparation is crucial for these patients. Close
communication between surgeon, anesthesiologist and the
transfusion staff of the blood bank before and during
surgery should be emphasized.
Acknowledgement: We are grateful to Prof. Victor Xia (Division
of Liver Transplant Anesthesia, Department of Anesthesiology,
University of California at Los Angeles) for linguistic comments
and editing this manuscript.
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Edited by CHEN Li-min
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