In 2006, the number of liver transplantations performed in the United States
6650,LT decreased slightly to 6494 in 2007.
As of early 2008, approximately 17,200 patients were on the waiting list for liver
transplantation in the United States; approximately 1600 to 1800 patients die
each year while awaiting liver transplantation.
Nationwide, the 3-year patient survival rate after transplantation is greater than
cirrhosis is likely to develop in 25% to 30% of the more than 4 million Americans
with hepatitis C.
Recurrent disease, especially with hepatitis C, necessitates retransplantation in
future years, which aggravates the acute organ shortage problem further.
PATHOPHYSIOLOGY OF END STAGE LIVER DISEASE
Chronic liver failure is infrequently associated with cerebral edema;
however, the encephalopathy found in chronic liver disease may
represent a common underlying pathophysiology.
The failure of hepatic clearance leads to the accumulation of toxins
such as ammonia and manganese, and to alterations in
endogenous transmitters and messengers, including g-aminobutyric
acid (GABA), glutamate and nitric oxide.
A hyperdynamic state, characterized by an elevated cardiac output and arteriolar
vasodilatation, occurs in up to 70% of patients with end-stage liver disease.
The clinical improvement seen after total hepatectomy in patients with acute liver
failure suggests that toxic substances released from the necrotic liver may be
As the criteria for transplantation is expanded, upper age limits for recipients
have been liberalized, making an evaluation for ischemic heart disease part of
the routine preoperative assessment.
Dobutamine stress echocardiography (DSE) is used in many centers to risk
stratify patients preoperatively. The advantages of DSE include the ability to
diagnose pulmonary hypertension and valvular heart disease.
The hyperdynamic circulatory state may resolve after transplant, though it has
persisted for several years. A recent study supports earlier work indicating that
cardiovascular risk is significantly elevated post transplant.
The pulmonary complications associated with liver disease include restrictive lung
disease,intrapulmonary shunts, ventilation-perfusion abnormalities and pulmonary
The restrictive disease results from ascites and/or pleural effusions and frequently responds to
fluid removal. Hypoxemia occurring in the absence of ascites or intrinsic lung disease is referred
to as hepatopulmonary syndrome.
This syndrome has been ascribed to shunting, ventilation-perfusion mismatch and/or diffusion
A contrast (bubble) echocardiograph is useful for defining the cause of room air hypoxemia. In
the presence of intrapulmonary shunting, microbubbles appear five or six beats after injection,
while in the presence of V/Q defects the bubbles are absorbed in the lung.
Pulmonary hypertension, defined as a mean pulmonary artery pressure > 25 mmHg in the
presence of a normal wedge pressure, occurs in up to 2% of patients with chronic liver disease.
Mild (mean PAP 25-35 mmHg) or moderate (mean PAP 35-45 mmHg) pulmonary hypertension
does not contraindicate transplantation, particularly in situations in which the pulmonary arterial
pressures are responsive to a pharmacologic trial of vasodilators.
Successful transplantation has been performed in patients with severe pulmonary hypertension
after long-term vasodilator therapy.Pulmonary hypertension has been reported to improve,
persist and even develop following liver transplantation.
The identification of patients with advanced renal disease needing combined liverkidney transplants (approx 5% of liver transplant recipients in 2004) is important
preoperatively, as is the treatment of preexisting acidbase abnormalities and
plasma volume defects, which might worsen less advanced renal disease in the
The predominant functional cause of renal failure in patients with hepatic failure is
hepatorenal syndrome (HRS). The diagnosis requires the absence of primary renal
disease, proteinuria, hypovolemia and hemodynamic causes of renal
hypoperfusion. A urinary sodium < 10 mEq/L and/or a fractional excretion of
sodium < 1% is typical.
The syndrome has been treated with success with vasoconstrictors, which improve
splanchnic vasodilatation, decrease endogenous vasoconstrictor levels and
improve renal blood flow. Caution should be used in patients with acute hepatic
necrosis, as cerebral blood flow has been shown to be adversely effected by
Nephrotoxic antibiotics and contrast used for diagnostic studies should be avoided
Cyclosporine adversely affects renal function postoperatively, typically decreasing
GFR by 30-50%.
Esophageal varices, portal hypertension and ascites are common.
Sclerotherapy and/or portosystemic shunts may be required.
Gastric emptying is delayed
Drug metabolism is affected.
End-stage liver disease patients tend to be sensitive to drugs, though they
may be resistant to some drugs (e.g., pancuronium) due to increased
binding to globulin.
The action of many drugs (such as opioids, lidocaine and propranolol) is
prolonged due to an increased volume of distribution and/or decreased
HEMATOLOGICAL AND COAGULATION
Anemia, due to chronic disease, malnutrition and/or bleeding, is
Coagulation defects result from the decreased synthesis of all
clotting factors except fibrinogen and factor VIII.
Splenic sequestration of platelets reduces the number of circulating
platelets, while a functional defect also occurs.
Ongoing fibrinolysis may occur due to low levels of antiplasmin and
inadequate clearance of tissue plasminogen activators.
Levels of procoagulant factors (II, V, VII, IX, X) and anticoagulant
factors (protein C and S, antithrombin III) are frequently decreased
in patients with end-stage liver disease
Thrombocytopenia as a result of hypersplenism, qualitative platelet
dysfunction, and disorders of the fibrinolytic system (reduced levels
of plasminogen, α2 -antiplasmin, and factor XIII and increased
plasma tissue-type plasminogen activator levels) is often
encountered during the perioperative period
Indications for Liver Transplantation
Viral hepatitis B and C
Inborn errors of metabolism
Primary sclerosing cholangitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Manipulation of the liver can impede venous return and result in
hypotension. Similarly, acute decompression of ascites early during
the dissection phase can result in hypotension.
During this phase, adequate fluid replacement is crucial, and
colloids are frequently used.
Diuresis should be established early during the procedure to
facilitate fluid management, and it may produce some renal
protection in anticipation of relative renal ischemia during the
anhepatic period .
pre-operative evaluation differ for an LT patient and a routine patient.
Pre-operative evaluation is performed in two stages. In the early first stage all LT
candidates are examined by anesthesiologists; the later, second-stage
evaluation is performed immediately before surgery.
One should plan for an operating room time of 8 to 20 hours , with an average
total time of 8.5 hours for anesthesia, 7 of which are devoted to surgery .
Acessing any neurologic deterioration since the initial first-stage evaluation is
necessary, and signs of progressive metabolic acidosis,infection or
sepsids,Cardiovascular instability, pulmonary infection and severe coagulopathy
should be corrected and treated.
Ideally, ascites should be controlled and nutrition improved, with prothrombin
time showing a return toward normal.
Coagulation status should be determined, and parenteral vitamin K should
be given at least 3 days pre-operatively if possible, although it is not always
possible to anticipate and schedule the operation (i.e., using cadaveric
Vitamin K administration corrects coagulation defects within 24±36 hours,
unless liver function is so poor that vitamin K-dependent proteins such as
Factor V and prothrombin can not be synthesized.
Albumin, fresh-frozen plasma, and cryoprecipitate can be given immediately
platelets can be infused (if the count is < 50,000/mm3) immediately after
Monitoring of temperature
Coagulation status should be monitored –platelet count ,fibrin degradation
products , prothrombin time , activated clotting time, partial
Thromboelastography has been used as a tool in liver transplantation.
Repeated BP cuff inflation –may lead to bruising in patients with altered
Insertion of Intra arterial line – care to prevent haematoma .
Jugular route is preferred in CVP monitoring.
Since coagulation may be abnormal pre-operatively, intramuscular
premedication is not advised.
Hepatic encephalopathy is another contraindication . If coagulation and level of
consciousness are normal, standard medications are not contraindicated.
The dose is usually adjusted downward because of reduced hepatic function,
including drug elimination. Premedication is frequently reduced or even omitted.
Pre- operative counseling for the patient's preparation and allows family
interaction with an alert individual before surgery.
However, if a patient so desires, short-acting benzo- diazepines are often
Rapid-sequence induction is performed because many of these patients have ascites
and, perhaps, the equivalent of a full stomach.
Delayed gastric emptying often exists in patients taking cyclosporine orally.
Thiopental 4 mg/kg, propofol 1-2 mg/kg, or etomidate 0.3-0.5 mg/kg, is used.
Succinylcholine 1-2 mg/kg is added to facilitate tracheal intubation while cricoid
pressure is maintained.
The induction agents are protein bound, and the free drug fraction is increased in liver
when serum albumin is low, leading to an enhanced effect.
Thiopental and etomidate are metabolized in the liver but their activity is terminated
by redistribution. Hence, their duration of action is normal unless the doses are large
Anesthetic maintenance is largely similar to that in other major abdominal
surgery. A narcotic can be successfully used in patients with hepatic
disease despite the pharmacologic consequences of decreased clearance
and prolonged half-life
Fentanyl, sufentanil and alfentanil are suitable opioid analgesic agents
because they have short half-lives and inactive metabolites.
fentanyl does not decrease hepatic oxygen and blood supply or prevent
increases in demand when used in moderate doses (50 mg/ kg bolus and
0.5 mg/kg/min infusions)
• INHALATION AGENTS
Halothane is avoided in favor of isoflurane for LT.
Halothane,enflurane and isoflurane all reduce liver blood flow, but halothane
reduces hepatic arterial flow to a greater extent .
The use of halothane is not advised because of its potenial to cause hepatic
damage. Nitrous oxide has been used for many years without increased
anesthesia-related postoperative hepatic complications.
However, it is often considered counterproductive because of its
sympathomimetic effect and accumulation in the intestinal lumen.
Another reason to avoid nitrous oxide is that potenial air emboli created
during the vascular anastomosis .
This stage begins with surgical incision and ends with the occlusion of flow through
the portal vein, inferior vena cava and hepatic artery.
This phase involves dissection and mobilization of the liver.
With abdominal incision and drainage of ascites, hypovolemia typically occurs. This
should be treated with colloid containing fluid to minimize preload changes. In the
presence of preexisting coagulopathy, fresh frozen plasma is indicated soon after
Thromboelastography (TEG) or standard laboratory tests (prothrombin time,
fibrinogen and platelet count) are used to guide the correction of coagulopathy.
Citrate intoxication, ionized hypocalcemia resulting from the infusion of citrate-rich
blood products in the absence of hepatic function, is avoided by the administration of
Ionized hypomagnesemia also results from citrate infusion.
Aggressive treatment of hypokalemia is best avoided, particularly in
preparation for reperfusion and the associated rise in potassium.
Supplemental glucose is usually not required, except in patients with severe
disease or those in fulminant hepatic failure.
The maintenance of urine output is desirable; however, the use of lowdose
dopamine for this reason is unproven.
Avoidance of hypothermia is important. Heated venovenous bypass during
the anhepatic phase permits core temperature control.
INTRAOPERATIVE MANAGEMENT, ANHEPATIC
This stage begins with the occlusion of vascular inflow to the liver and ends with graft
reperfusion. Occlusion of the vena cava reduces venous return by as much as 50%.
Venovenous bypass, which diverts inferior vena cava and portal venous flow to the axillary vein,
attenuates the decrease in preload, improves renal perfusion pressure, lessens splanchnic
congestion and delays the development of metabolic acidosis. The use of venovenous bypass
is not without risk.
Air embolism, thromboembolism and inadvertent decannulation may be fatal or result in
significant morbidity. Venovenous bypass is not uniformly used at all centers.
Hepatectomy is followed by vascular anastomoses of the supra- and infra-hepatic IVC and the
Fibrinolysis may begin during this stage due to an absence of liver produced plasminogen
activator inhibitor resulting in the unopposed action of tissue plasminogen activator.
The reperfusion of the graft begins the neohepatic stage. Reperfusion is typically via
the portal vein, though the sequence of revascularization may have implications.
Reperfusion is associated with abrupt elevations in potassium and hydrogen ion
concentrations, an increase in preload and a decrease in systemic vascular
resistance and blood pressure.
Hypothermia, monitored via blood Temperature, is a marker for the presence of graft
outflow into the central circulation.
Potentially life-threatening hyperkalemia requires calcium chloride and possibly
bicarbonate administration. However, even in the absence of treatment, elevated
potassium levels fall spontaneously within minutes due to redistribution. The
presence of EKG changes suggestive of hyperkalemia requires prompt treatment.
Fibrinolysis is most severe after reperfusion. Antifibrinolytics and cryoprecipitate may
The hepatic arterial anastomosis and biliary reconstruction are generally performed
after venous reperfusion.
Signs of graft function that may be observed in the operating room include decreased
calcium requirements, improvement in acidosis, increased urine output, a rising core
temperature and bile output from the graft.
• Biliary atresia is the most common primary diagnosis in pediatric liver
transplant recipients, while metabolic liver disease represents the
second largest group.
• Bleeding may not be severe in these patients because synthetic function
is usually preserved.
The risk of hepatic artery thrombosis in children leads to less vigorous
correction of any clotting defects. Fresh frozen plasma is used sparingly
and antifibrinolytics are typically avoided.
A major limitation to clinical transplantation is the availability of organ donors.
Avoidance of damage to the graft during the procedure are essential in securing
optimal function of the transplant.
aggressive donor management protocols to minimize the adverse physiologic
consequences of brain death. These protocols include respiratory and hemodynamic
support, adequate fluid resuscitation, and the initiation of hormone replacement.
Brain death is associated with significant instability, and minute-to-minute
management by experienced personnel in the intensive care unit (ICU) is necessary
to ensure adequate perfusion of all organs.
the donor's liver function must be determined. Rapid screening and serial follow-up of
liver enzymes and synthetic function are performed to determine the degree of liver
injury and predict the potential for recovery.
Routine assessment for diseases that might be transmitted by the liver graft must
include hepatitis screening, as well as any history of the use of toxic substances such
as long-standing alcohol consumption.
Although donor age has been shown to have an adverse impact on outcome, most
programs now consider the use of donors up to 75 or 80 years of age. This approach
has been necessary because of the desperate need for lifesaving organs and is
supported by scientific evidence of a relatively slow aging process occurring within
the liver parenchyma.
It also appears that grafts from donors with serology positive for a pathogen present
in the recipient (i.e., hepatitis B or C) can be used with results equal to those of
transplantation with uninfected grafts, as long as the liver does not have established
severe hepatitis or fibrosis.
Donor and recipient matching are based on ABO blood group compatibility and size.
However, these barriers may be crossed when transplantation is urgent.
Most surgeons try to match donor-recipient age for pediatric recipients because
variation may have an impact on long-term graft survival.
LIVING DONOR TRANSPLANTATION
Initial reports about LDLT in the early twentieth century established technical
feasibility of the procedure .
The donor hepatectomy can include left lobes, left lateral segments , or
extended right lobe. LDLT has some advantages for the pediatric recipient
and the transplant population as a whole.
These include increased graft availability and survival, and decreased
morbidity, mortality, rejections, and cost.
Potential donor evaluation should include bedside ABO blood type
compatibility with the recipient (the only need in a cadaveric donor). Also
necessary is the exclusion of acute, chronic or viral illness, and liver/biliary
system function and anatomy assessment, as well as psychological
Although the procedure is relatively safe for the donor, over 10% of donors
have presurgical complications . Surgical experience and technical
modifications have resulted in significant reduction of these complications.
The mortality risk of hepatic resection in non-cirrhotic individuals is
extremely low when the operation is performed in an experienced
SPLIT CADAVERIC-DONOR GRAFT
LT in small children has been limited by the shortage of suitable
cadaveric donor organs.
The number of new transplant candidates under 5 years of age has
increased by 5% annually since 1988, while the annual number of
CD transplants performed in this age group has fallen
The split is done between the adult recipient, (using the extended
right lobe), and the pediatric recipient (using the left lobe) of the CD
Split CD graft was the obvious technical solution to this problem of
pediatric graft availability.
However, in high urgency patients where emergency OLT was
needed, and the technique of emergency living donor liver
transplant could not be applied or was not yet developed (i.e., prior
to 1999) , split CD transplantation of two grafts was the only
NEW IMMUNOSUPPRESSIVE DRUGS
Cyclosporin is the most commonly used maintenance immunosuppressive drug.
Steroids are almost invariably added .
Azathioprine may be used as a third agent to reduce the dose of cyclosporine and, in
some cases, may replace cyclosporine altogether when the latter is contraindicated
or can no longer be used because of adverse side effects.
Anti-lymphocyte globulin preparations, including the monoclonal antibody OKT-3 ,
have been given prophylactically and for specific indications to prevent rejection.
OKT-3 reacts against all mature T lymphocytes.
The most prominent is tacrolimus (FK506), which became an established immunosuppressant agent for primary and rescue therapy (when experiencing rejection or
poor tolerability to cyclosporin) in patients with liver, kidney and pancreas transplants.
FULMINANT HEPATIC FAILURE
Fulminant hepatic failure is an uncommon entity with the potential for rapid
progression to coma. Cerebral edema and elevated intracranial pressure occur in up
to 80% of patients with acute liver failure. The combination of coagulopathy and
altered mental status is ominous, particularly, when associated with a decrease of
previously elevated liver enzyme values.
In patients with stage III or IV coma, intracranial pressure monitoring should be
considered. Fresh frozen plasma and platelet concentrates are indicated prior to ICP
monitor placement when the INR is > 2 or the platelet count is < 50,000, or in the
presence of clinically significant microvascular bleeding.
The cerebral perfusion pressure should be maintained above 50 mmHg.
Administration of diuretics, elevation of the patient’s head 10-20 degrees,
maintenance of the arterial pressure and treatment of agitation are important in
maintaining cerebral perfusion pressure.
Postsurgical pain control is not generally a problem. Several studies
have shown that analgesic requirements in patients with end-stage
liver disease undergoing liver transplantation appear to be
significantly decreased compared with other major abdominal
In one study, the neuropeptide metenkephalin, which is involved in
pain modulation, was shown to be significantly elevated in liver
transplant patients compared with the control population.
The exact mechanism of this clinical observation is unknown, and
preoperative administration of large doses of steroids may play
Recovery can range from uncomplicated to extremely complex.
Frequent assessment of cardiac and pulmonary function, serum glucose
and electrolytes, renal and liver function, and coagulation and the blood
count is crucial.
Certain aspects require special attention, Patients occasionally need fresh
frozen plasma therapy postoperatively to offset an initially low graft liver
Fresh frozen plasma requirements also are considered an indirect measure
of postoperative liver function.
Leakage from vascular anastomosis sites, or “bleeders,” and diminished
flow or thrombosis in the hepatic artery or portal vein should always be
Patients who have adequate postoperative liver function and have received
steroids tend to be hyperglycemic, which may warrant an infusion of insulin.
The one-year patient and graft survival rates reported in the 2006 was 88% and 83%,
respectively. The three-year patient and graft survival rates were
Repeat transplantation is associated with a decrease in patient survival compared to
primary transplants. Similarly, decreased survival is also seen in patients transplanted
from the ICU.
Patient survival after CD transplant is decreased compared to donation after brain
death (DBD) transplants, though the difference in survival between the two groups
appears to be diminishing.