Haemostasis Disorders Clinical Trial
Official title:
Investigation of Systemic and Regional Haemostasis During Liver Transplantation by Comparing ClotPro® and TEG ® Viscoelastic Tests
The purpose of the research is to compare the global and the portal haemostasis during liver transplantation by functional investigations using TEG® and ClotPro® tests. The study aims at revealing important coagulation-associated links affecting the outcome of the liver transplant surgery.
Donor data Liver donor data are investigated following the "Donor Query" used for donor
reports of the Organ Coordination Office of the Hungarian National Blood Transfusion Service.
(http://www.ovsz.hu/sites/ovsz.hu/files/szervadomanyozas_dokumentum/donacio/donorlekerdezo-20
13-06-03.pdf) The donor is identified by the alarm ID and the Eurotransplant number (ETnr).
Independently of this study, the "Donor Query" is completed for all donor reports and helps
to asses donor suitability.
Recipient preoperative data In case of a liver alarm, age, body metrics, medical history,
type and severity of hepatic disease, concomitant diseases, and admission laboratory test
results of the recipient are recorded. Independently of this study, these data/procedures are
recorded/performed for all liver transplant candidates.
Surgical data In addition to technical data of the surgery, data on intraoperative fluid
balance, transfusion need, supportive therapy (vasopressor or inotropic therapy, renal
replacement therapy), and number and indication of any reoperation are also recorded.
Intraoperative sampling times and investigations
During a liver transplantation, independently of this study, the following procedures are
performed to monitor the patient's haemodynamics, homeostasis, and haemostasis:
- femoral artery catheterisation by pulse index contour cardiac output (PiCCO) catheter -
haemodynamic monitoring by PiCCO
- radial artery catheterisation - arterial blood gas and arterial pressure monitoring
- subclavian or internal jugular vein catheterisation - central venous pressure (CVP) and
central venous blood gas monitoring, drug administration
- external jugular vein catheterisation - blood sampling for haemostasis tests (TEG® and
ClotPro® conventional laboratory tests - international normalized ratio (INR), activated
partial thromboplastin time (aPTT), fibrinogen, antithrombin (AT), factor V (FV), factor
VII (FVII), factor X (FX), factor XIII (FXIII)
- 2 3 large peripheral veins - fluid resuscitation
- permanent urinary catheter - hourly urine output
During the study, for the analysis of haemostasis (TEG®, ClotPro®) and blood gases, 3.5 ml
blood will be sampled per site and time from the external jugular vein catheter representing
the systemic sample and from the portal vein representing the regional sample. Before
performing the portal vein anastomosis, a small amount of blood is routinely flushed from the
portal vein. Regional blood sampling is performed from this blood.
Systemic sampling is performed five times:
- before the surgery (S1)
- during the hepatectomy, 10 minutes before the anhepatic phase (S2)
- in the anhepatic phase, before starting portal vein anastomosis: (S3)
- in the neohepatic phase, 15 minutes after releasing portal vein clamping: (S4)
- in the neohepatic phase, at the end of the surgery: (S5)
Regional sampling from the portal vein is performed once:
• in the anhepatic phase, before starting portal vein anastomosis: (R)
Simultaneously with haemostasis and blood gas analyses, the following investigations will be
performed (as the part of the anaesthesia protocol):
- haemodynamic measurements by PiCCO
- arterial blood gas analysis from radial artery catheter
- central venous blood gas analysis from subclavian vein catheter
- blood temperature measurement in the femoral artery by PiCCO catheter
- hourly urinary output Postoperative phase and follow-up In the immediate postoperative
phase, postoperative heamodynamic, pulmonary, renal function, liver graft function) and
their supportive therapy will be analysed.
Laboratory tests (quantitative and qualitative blood count, INR, aPTT, fibrinogen, AT, FV,
FVII, FX, FXIII, C reactive protein (CRP), procalcitonin (PCT), electrolytes, creatinine,
urea, bilirubin, liver enzymes, albumin, total protein, immunosuppressive drug levels) will
be performed at the end of the surgery, at postoperative hours 12 and 24, on postoperative
days 2, 3 and 7. As far as possible these tests will be carried out on day 30 and one year
after the surgery as well.
Vasopressor and inotropic therapies will be analysed. The duration of assisted ventilation
and the presence of pleural fluid or any sign of postoperative pneumonia will be evaluated.
Urinary output as well as need for renal replacement therapy and the modality of that will
also be investigated. Liver graft function will be monitored by means of laboratory
parameters and graft perfusion with sonography. Initial poor function (IPF) and primary
nonfunction (PNF) During the study, one-year graft and patient survival rates, the occurrence
of small bile duct complications associated with arterial perfusion disorders, and the
recurrence of underlying hepatic disease will be recorded. If a biopsy is taken within one
year, histopathological results will also be evaluated.
Methodology and organisation of the study Informing patients on the study will occur during
liver alarms by an anaesthesiologist. One copy each of the Patient Information Leaflet and
the Informed Consent Form signed by the patient, the consenting physician and the principal
investigator will be given to the patient. A copy of each of them will be filed in the
medical records of the patient and the original one will be part of the research
documentation.
During the study, tests for the investigation of parameters described in the protocol will be
performed by the patients' physicians and other health care professionals involved in patient
care.
Coagulation tests During the study, viscoelastic tests will be performed by TEG® and ClotPro®
instruments.
Blood sampling for systemic TEG® and ClotPro® tests will be performed from the routinely
catheterised external jugular vein while blood for regional tests will be taken from the
portal vein of the recipient. After obtaining informed consent from the patient, 3.5 mL of
blood samples will be collected in citrate tubes designated for the study at surgery phases
described above. Investigations will be conducted by a TEG® 5000 thromboelastograph
(Haemonetics Corp., Switzerland) and a ClotPro® (enicor GmbH, Germany) analyser. Results will
subsequently be analysed by computed statistical tests. Simultaneously with viscoelastic
tests, blood gas analyses will also be performed from the collected blood samples to obtain
current pH, pCO2, and bicarbonate and calcium levels and their role in coagulation will be
considered for the study. Furthermore, central body temperature will also be continuously
monitored and recorded during the perioperative phase.
During TEG® and ClotPro® measurements in this study, the following parameters will be
compared:
for TEG®, the following parameters will be considered in the study: R (reaction time): fluid
phase of coagulation, time to formation of 2 mm clot; K (kinetics): time to formation of 20
mm clot; α: angle between 2 mm and 20 mm clot; MA (maximum amplitude): ultimate size of the
clot; Ly30: percent rate of lysis at 30 minutes post MA. During the liver transplantation
citrated kaolin test (CK-TEG) will be completed.
for ClotPro®, the following parameters will be considered in the study: CT (clotting time):
indicates the fluid phase of coagulation (corresponds to R in TEG®); CFT (clot formation
time): coagulation kinetics parameter, time between formation of 2 mm and 20 mm clot
(corresponds to K in TEG®); α: angle (slope) of line between CT and CFT; A10 and A20 describe
clot size (amplitude) at certain time points; MCF (maximum clot firmness): represents the
ultimate size (maximum amplitude) of the clot (corresponds to MA in TEG®); clot lysis index
at 30 (CLI30) describes the ratio between the maximum clot firmness and the amplitude 30
minutes after clotting time, LT (lysis time): characterises tPA effect.
During the liver transplantation EX-test, IN-test, FIB-test, TPA-test, RVV-test, and ECA-test
tests will be completed.
Blood gas analyses Analyses are currently done by a GEM® PremierTM 3500 instrument. The blood
gas analyser measures the following parameters: pH, pCO2, pO2, sodium, potassium, ionised
calcium, blood glucose, lactate, bicarbonate, base excess, haemoglobin, haematocrit. Blood
gas analyses are performed from the arterial and central vein samples. From the portal vein,
blood sample is collected by the surgeon.
Laboratory parameters The following parameters will be measured at the laboratory by Sysmex
CS 2000i, Sysmex XN-1000 (Sysmex Europe GmbH, Hungary) and Dimension® RxL Max® Integrated
Chemistry System (Siemens Healthcare GmbH, Hungary)
- quantitative and qualitative blood count
- INR, aPTT, fibrinogen, AT, FV, FVII, FX, FXIII, sodium, potassium, magnesium, phosphate,
ionised calcium
- creatinine, urea
- CRP, PCT
- total and direct bilirubin
- albumin
- liver enzymes: alkaline phosphatase (ALP), glutamic-oxaloacetic transaminase (GOT),
glutamate-pyruvate transaminase (GPT), gamma-glutamyltransferase (GGT), lactate
dehydrogenase (LDH), cholinesterase
- pancreatic enzymes: amylase, lipase Time of each laboratory test is determined by the
study protocol. Laboratory tests associated with this study do not differ from the
current clinical practice and thus, pose no additional interventions over the standard
care.
Haemodynamic parameters Haemodynamic monitoring is performed for all patients undergoing
liver transplantation in the perioperative period, independently from this study. Monitoring
is done by a PiCCO instrument. During thermodilution measurements, cardiac output (CO),
cardiac index (CI), intrathoracic blood volume index (ITBI), extravascular lung water index
(EVLWI), stroke volume (SV), stroke volume variation (SVV), cardiac function index (CFI),
maximum left ventricular contractility (dPmax), and mean arterial pressure (MAP) will be
monitored.
CVP will be monitored via the catheterised subclavian vein. Time of each haemodynamic test is
determined by the study protocol. Haemodynamic tests associated with this study do not differ
from the current clinical practice and thus, pose no additional interventions over the
standard care.
Oxygen delivery and consumption Parameters characterising oxygen delivery (oxygen delivery
index; DO2I) and consumption (oxygen consumption index; VO2I) are calculated from arterial
and central venous blood gas analysis results and from haemodynamic parameters.
Statistical methods Statistical analyses will be performed by Social Sciences software (SPSS;
SPSS Inc, Chicago, Illinois, USA).
Continuous and discrete variables will be analysed by independent samples t tests (two
categories) and one-way analyses of variance (one-way ANOVA; more categories), respectively.
Two continuous variables will be compared by Spearman's rank correlation test. Discrete
variables will be tested by Pearson's Chi squared test. Ordinary variables will be compared
by Mann-Whitney U test or Kruskal-Wallis test. For multivariate analyses, logistic regression
models will be generated.
Significance level will be set to 5% (p ≤ 0.05).
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