liver transplant med

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This activity is made possible by an unrestricted educational grant from FujisawaHealthcare, Inc.

March 28, 2003

The objectives for this chapter are to:

Describe the current status of liver transplantation;

List underlying diseases and conditions that may result in the need for liver transplantation;

Identify patient populations that may benefit from liver transplantation;

Outline key steps in the evaluation of patients for liver transplantation;

Summarize current recommendations for immunosuppression in liver transplantation;

List the most common postoperative complications of liver transplantation; and

Discuss recent advances in treatment and management of liver transplant recipients.

The road to successful liver grafting in humans has been a long one, fraught with many obstacles. Experimental attempts

at liver transplantation took place in the 1950s and 1960s,[1-5] but human liver transplantation did not become a reality until

1963.[6] Although unsuccessful, Dr. Starzl's accomplishment was a milestone in surgery, as was the first successful

human orthotopic liver transplantation (OLT) [see footnote] in 1967,[7] which he attributed to the addition of antilymphocyte

globulin (ALG) to the immunosuppressive regimen.

By 1983, most of the technological challenges of OLT had been conquered, but the challenges of the immune system

remained. In 1983, the National Institutes of Health (NIH) held a Consensus Development Conference on Liver

Transplantation. The most important outcome of this conference was that OLT was considered an accepted therapeutic

modality for some patients with end-stage liver disease (ESLD).[8] At the time of this conference, there was only 1 liver

transplant center in the United States (University of Pittsburgh) with a sizable patient experience. Currently, 120 liver

transplant centers are registered with the United Network for Organ Sharing (UNOS). The growth of OLT, in numbers

alone, is staggering. In 1981, just 26 procedures were performed in the United States[9]; by 1988, approximately 2000

had been performed in the United States and another 1000 throughout the rest of the world.[10] Based on OPTN data for

2002, 5325 liver transplants were performed for all age groups in the United States, bringing the total number of

transplants performed to date in the United States to 56,119.

Since the first OLT was performed in 1963, the field has changed dramatically as a result of improvements in surgical and

anesthetic and management, postoperative care, organ preservation, and immunosuppressive therapy. The development

of cyclosporine (CsA) in the late 1970s as a powerful immunosuppressive agent was one of the most significant events in

modern transplantation. In the pioneering days of OLT, triple-drug therapy (corticosteroids, azathioprine [AZA], and ALG)

was used to prevent and treat rejection. By 1984, all transplant centers in the United States were using double therapy,

consisting of corticosteroids and CsA, as the maintenance immunosuppressive regimen.[11] During the 1990s, tacrolimus

(TAC) emerged as the mainstay maintenance immunosuppressive agent, with or without corticosteroids, in OLT. More

recently, mycophenolate mofetil (MMF) has replaced the use of AZA in many centers.

Before the advent of CsA, 5-year survival after OLT was less than 20%.[12] Currently, the overall 3-year survival (76%) is 3

times higher than with conventional AZA plus corticosteroid immunosuppression.[13] One- and 5-year patient survival rates

Liver Transplantation

Cosme Manzarbeitia, MD, Susan L. Smith, MN, PhD

http://www.medscape.com/viewarticle/451209_print

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after OLT now approach 90% and 80%, respectively, and corresponding graft survival rates approach 85% and 75%,

respectively. Graft survival is lower than patient survival because some patients require retransplantation.

Other factors responsible for earlier increased success of OLT include advances in surgical techniques, particularly the

standardization of biliary tract reconstruction, and advances in retransplantation; advances in surgical technology, such as

pump-driven venovenous bypass that did not require recipient heparinization,[14] rapid infusion and autologous

auto-transfusion devices; improved procurement and preservation techniques for the donor liver; and increased insight

into the management of potentially fatal complications.

After careful study of the results of OLT, it has become clear that survival is affected by numerous preoperative,

intraoperative, and postoperative factors. Understanding the risk factors for poor outcome is therefore of paramount

importance. Preoperative factors such as age greater than 60 years, concomitant comorbid conditions (eg, cardiac and

pulmonary disease), degree of hepatic decompensation at the time of transplantation, presence of renal failure, severe

malnutrition, and need for life support all influence survival. The etiology of the patient's liver disease also influences

survival, as is evidenced by the lower survival rates associated with OLT performed for acute fulminant hepatic failure

(AFHF) or hepatoma. Surgical risk factors include the presence of prior surgery (especially right upper quadrant surgery or

prior OLT), presence of portal vein thrombosis (PVT), and obesity. Postoperative factors adversely affecting survival

include technical complications such as hepatic artery thrombosis (HAT), primary nonfunctioning graft (PNFG) leading to

posttransplant AFHF, sepsis, and complications of immunosuppression.

Despite these problems, the majority of OLT recipients enjoy excellent long-term quality of life. As a general rule,

immunosuppression is gradually reduced and ancillary prophylactic medications are reduced or discontinued over the

course of the first year posttransplantation. By 1 year posttransplantation, most patients are receiving a minimum number

of medications, thus improving the chances of long-term compliance. Most recipients are physically and emotionally

healthy, can normally perform activities of daily living, and are able to maintain steady employment. Furthermore, female

OLT recipients may safely bear children;however,it is generally recommended that women wait 1-2 years after OLT before

attempting conception until they are on minimal maintenance immunosuppression and past the high-risk period for acute

rejection.

* Two fundamentally different surgical approaches to liver transplantation exist: (1) orthotopic (OLT), and (2)

heterotopic (HLT). In OLT, the patient's diseased liver is completely removed and replaced by a donor liver with

normal or near-normal anatomic reconstruction. In HLT, the patient's diseased liver is left in place and an auxiliary

liver is grafted into an ectopic site. The first attempts at liver transplantation were heterotopic to avoid sacrifice of

functional hepatic reserve should the graft fail or reject. Currently, experimental indications for HLT include treatment

of the patient with acute fulminant hepatic failure and the patient who has had surgery in the right upper quadrant that

prohibits OLT. For purposes of this chapter, liver transplantation will be referred to as OLT unless otherwise noted.

The adult liver is the second largest organ in the body, weighing 3-4 pounds in the average adult. The liver is located in the

right upper quadrant of the abdomen, below the ribs. Chronic disease of the liver causes it to scar and shrink, leading to a

condition known as cirrhosis. Scar tissue within the liver blocks the forward flow of blood through the organ, leading to

portal hypertension (manifested by ascites, variceal bleeding, encephalopathy, and hypersplenism) and decreased

synthetic and metabolic function (manifested by wasting, coagulopathy, and low albumin).

Cirrhosis, the seventh leading cause of death by disease in the United States, has many origins. The majority of diseases

that lead to cirrhosis primarily affect the hepatocytes (hepatocellular diseases): alcoholic liver disease (ALD) and

postnecrotic cirrhosis (PNC). In the United States, ALD is the most common cause of cirrhosis. PNC may result from

chronic viral hepatitis B, C, or D.

Liver injury leading to cirrhosis also may be caused by a number of inherited diseases such as cystic fibrosis, alpha-

1-antitrypsin deficiency, hemochromatosis, Wilson's disease, galactosemia, and the glycogen storage diseases.

Diseases that interrupt the normal flow and production of bile (cholestatic diseases) can also lead to cirrhosis. In

newborns, the most common cause of cholestatic cirrhosis is biliary atresia, characterized by undeveloped or fully absent

bile ducts. In adults, the bile ducts may become inflamed, blocked, and scarred due to either primary biliary cirrhosis

(PBC) or primary sclerosing cholangitis (PSC). Traumatic or surgical injury to the bile ducts is called secondary biliary

cirrhosis.

Other less common causes of cirrhosis are drug reactions, prolonged exposure to environmental toxins, chronic

Budd-Chiari syndrome, and long-standing congestive heart failure leading to passive hepatic congestion. Though it is


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beyond the scope of this chapter to discuss in depth each of these disease processes, the reader is encouraged to do

so to develop a full appreciation for and understanding of the full scope of chronic liver disease. The reader is referred to

"Patients with Liver Dysfunction" in Critical Care Nursing for a comprehensive discussion of care of the patient with liver

disease.[15]

The indications for and contraindications to liver transplantation continue to evolve. A candidate for OLT must have

irreversible acute or chronic ESLD that is refractory to other forms of conventional medical or surgical therapy. Current

indications for OLT ( ) in adults include advanced cirrhosis resulting from hepatocellular disease, cholestatic syndromes,

metabolic liver disease, unresectable hepatic malignancies, and AFHF. The most common disease indication in adults is

chronic hepatitis C virus (HCV) infection; in children, biliary atresia and alpha-1-antitrypsin deficiency are the most common

indications. In addition, there must be no absolute contraindications to OLT.

Table 1. Disease Indications for Liver Transplantation

Advanced Chronic Liver Disease

Predominantly cholestatic disease

Biliary atresia

Primary biliary cirrhosis

Primary sclerosing cholangitis

Familial cholestatic syndromes

Predominantly hepatocellular disease

Chronic viral-induced liver disease (hepatitis B, C, D)

Chronic drug-induced liver disease

Alcoholic liver disease

Idiopathic autoimmune liver disease

Predominantly vascular disease

Budd-Chiari syndrome

Veno-occlusive disease

Unresectable Hepatic Malignancies

Hepatocellular carcinoma

Cholangiocarcinoma (highly selected cases, only under protocol)

Rare nonhepatocellular or bile duct tumors that arise within the hepatic parenchyma (eg, epithelioid

hemangioendothelioma)

Isolated hepatic metastatic disease

Carcinoid tumor

Pancreatic islet cell tumor

Metabolic Liver Disease

Alpha-1 antitrypsin deficiency

Wilson's disease

Homozygous type II hyperlipoproteinemia

Crigler-Najjar syndrome type I

Erythropoietic protoporphyria

Urea cycle deficiencies

Glycogen storage diseases, type I and IV

Tyrosinemia

Hereditary hemochromatosis

Fulminant Hepatic Failure

Acute viral hepatitis (A, B, D, non-A, non-B, Epstein-Barr virus EBV)

Drug-induced liver toxicity


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Halothane

Gold

Disulfiram

Acetaminophen

Others

Metabolic liver disease

Wilson's disease

Reye's syndrome

Organic acidurias

It is estimated that HCV infects more than 100 million people worldwide. HCV-related disease is the most common

indication for OLT in the United States (accounting for approximately 40%) and Europe. Five-year patient and graft survival

rates after OLT for HCV infection are comparable to survival rates associated with other conditions.[16] The downside is

that OLT is not curative for this indication and posttransplant recurrence, as determined by detection of HCV RNA, is

universal, and approximately 50% have histologic evidence within the first posttransplant year. Exposure to corticosteroids

is a risk factor for worse outcomes. Cumulative exposure is associated with higher levels of HCV viremia, more severe

histologic changes, and increased mortality. Approximately 10% of patients who develop histologic evidence of recurrent

HCV infection die or require retransplantation within 5 years.

Therapy with interferon and ribavirin has proved to be moderately effective, producing sustained virologic response in

30% of genotype 1 patients.[17] Weekly treatment with peginterferon alfa-2a has produced similar response rates in

genotype 1 patients. Research is ongoing to develop antiviral agents that will prevent or delay disease progression and is

also focused on how to make the currently available therapies more tolerable in order to increase patient adherence to

regimens.

Significant improvements in patient and graft survival after OLT for hepatitis B virus (HBV)-related disease have been

made during the last decade. Fifteen years ago, chronic HBV infection had the poorest outcome among all cases of

patients with nonmalignant disorders undergoing OLT due to disease recurrence. Patients with active viral replication at

the time of transplantation have the greatest risk of reinfection.[18]

Outcomes changed, however, with the recognition that long-term administration of high-dose hyperimmune globulin

improved patient and graft survival and virtually eliminated the most aggressive manifestation of HBV infection after

transplantation, fibrosing cholestatic hepatitis. Use of hepatitis B immunoglobulin (HBIg) is now universal, usually in

combination with lamivudine. However, this therapeutic approach is hindered by the high associated costs, low patient

tolerability, and the inconvenience of monthly intravenous injections of 10,000 IU HBIg.

The Australia-New Zealand liver transplant group has pioneered the use of lower doses of HBIg administered

intramuscularly in combination with lamivudine. Gane and colleagues[19] reported on 107 patients who were HBV surface

antigen-positive and underwent OLT between February 1996 and April 2002. Any patient who was HBV DNA-positive

before transplantation received lamivudine 100 mg daily until transplantation for a median of 63 days. The median

posttransplantation follow-up was 803 days. The posttransplantation antiviral protocol consisted of oral lamivudine 100 mg

daily, plus HBIg 400 or 800 IU by intramuscular injection daily for the first 7 postoperative days, followed thereafter by the

same dose monthly indefinitely. Patient survival was 90% at 1 year and 80% at 5 years, findings that were identical to

those observed in patients who were not infected with HBV. The HBV disease-free survival was 98% at both 1 and 5

years. The adoption of the low-dose protocol results in associated cost savings of approximately $50,000 per annum. It

remains uncertain whether HBIg can be stopped and adequate protection maintained with lamivudine alone.

As long-term survival improved, the absolute and relative contraindications to OLT changed, steadily becoming fewer. At

the time of the NIH Consensus Development Conference, contraindications included alcoholism, tumors other than

primary hepatic tumors, and psychosocial and economic factors such as inability to understand the implications of the

procedure or inability to pay. However, patients with all of these conditions and/or situations are now transplanted on a

case-by-case basis. Absolute contraindications are conditions in which the outcomes of liver transplantation are so poor

that it should not be offered. Relative contraindications are conditions that have a negative impact on survival, but not to

the extent that they should be categorically withheld.

The combination of preexisting local or systemic infection outside the hepatobiliary system (such as peritonitis,

pneumonia, or bacteremia) and the necessity of postoperative immunosuppressive therapy place the patient at great risk


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for a fatal infection and, therefore, preclude successful liver transplantation. Likewise, because the operative procedure is

so physiologically rigorous, significant cardiovascular or pulmonary disease decreases the likelihood of surviving the

perioperative or postoperative period. In general, contraindications include compensated cirrhosis, extrahepatic

malignancy, severe and uncontrolled extrahepatic infection, advanced cardiopulmonary disease, multisystem organ failure,

active substance abuse, and anatomic abnormalities that preclude performing the surgical procedure of liver

transplantation.

Malignancy is a problem that requires careful consideration in the evaluation of the liver transplant candidate. Ironically, the

initial indications for human OLT mandated that the patient have a hepatic malignancy. The rationale was that because of

the highly experimental nature of the procedure and low survival rates, it was not justifiable to subject a patient with

non-neoplastic disease to the procedure. Today, however, advanced hepatic malignancy (greater than stage III) is, in most

cases, considered a contraindication to OLT.

Primary hepatic tumors are epithelial, mesenchymal, or mixed in origin. Of these, epithelial tumors are the most common

and include hepatocellular carcinoma (HCC), cholangiocarcinoma, mixed hepatocholangiocarcinoma, hepatoblastoma,

and a number of other rare tumors.

There is no effective chemotherapy for most types of liver tumors, and the resectability rate is quite low. Thus, OLT

represents the only possible therapy for most patients with a primary malignancy of the liver. The surgical procedure for

this group of patients is generally simpler from a technical perspective than in patients with ESLD because the clinical

picture of a patient with a malignant liver tumor is much different from that of the typical patient evaluated for OLT. Unlike a

patient with ESLD, a patient with a primary hepatic malignancy who is in relatively good physical condition does not have

cutaneous stigmata of advanced liver disease and usually has well-compensated cirrhosis with absent or mild portal

hypertension.

Hepatocellular carcinoma (HCC). HCC is a malignant tumor derived from hepatocytes and frequently occurs in association

with chronic liver disease, especially cirrhosis. Liver transplantation for early-stage (stage I and II with a negative

metastatic workup) HCC is associated with survival rates comparable to those when OLT is performed for other

indications. In most cases, liver transplantation is preferable to resection of HCC, particularly in the presence of underlying

cirrhosis, but tumor progression and/or death while awaiting transplantation is a significant problem. And,

immunosuppressive regimens necessary for prevention and treatment of rejection are thought to accelerate tumor growth.

Using the Milan criteria,[20] 3-year posttransplant survival was 83% with only 8% recurrence if transplantation was

performed for a single HCC < 5 cm in diameter, or for up to 3 separate HCC lesions, each < 3 cm in diameter. The

recurrence rate of HCC found incidentally at the time of transplantation is very low.

The Model for End-Stage Liver Disease (MELD)[21] scoring system, discussed in the section Medical Necessity below,

has recently been applied to patients with HCC awaiting liver transplantation. A priority MELD weight of 24-29 points is

given to patients with HCC who met the Milan criteria while awaiting transplantation. Under this system, transplantation in

patients with HCC increased 3.5-fold over a corresponding time interval from the prior year; 86% to 91% of patients with

HCC received a transplant within 3 months of being issued a priority MELD score. There has been no detectable trend

toward increased use of priority scores to obtain transplants on a preferential basis. Analysis of the Milan criteria and other

systems will continue in an effort to refine criteria for entry of patients with HCC into the UNOS liver transplant waiting list.

Cholangiocarcinoma. Sclerosing cholangitis, a major indication for OLT, is frequently associated with cholangiocarcinoma.

Cholangiocarcinoma is an intrahepatic malignant tumor consisting of cells that resemble biliary epithelium. OLT for

patients with cholangiocarcinoma has historically been controversial, and such treatment has been abandoned by most

programs. When performed alone for unresectable cholangiocarcinoma, OLT is often associated with early disease

relapse and limited survival. However, a small percentage of patients have achieved prolonged survival after OLT,

suggesting that adjuvant approaches could perhaps improve the survival outcome. Encouraging results have been

published by the Mayo Clinic group.[22] A small group of patients with unresectable cholangiocarcinoma above the cystic

duct without intrahepatic or extrahepatic metastases received external-beam irradiation plus bolus fluorouracil (5-FU),

followed by brachytherapy with iridium and concomitant protracted venous infusion of 5-FU. The authors concluded that

OLT in combination with preoperative irradiation and chemotherapy is associated with prolonged disease-free and overall

survival in highly selected patients with early-stage cholangiocarcinoma.

Metastatic malignancy. Survival after OLT for metastatic disease is rare. Because the liver is the organ most frequently

associated with metastatic tumors, before any patient undergoes OLT for malignant hepatic disease, every attempt is

made to rule out metastatic disease. Computed tomography (CT) of the abdomen, lungs, and head; chest x-ray


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evaluation; nuclear magnetic resonance imaging (MRI); bone scanning; and other tests are commonly performed.

Unfortunately, micrometastases are frequently undetectable and may not be discovered until abdominal exploration at the

time of surgery. For patients with a high index of suspicion for metastatic disease, despite workup findings that do not

confirm the diagnosis, it is common practice to explain to the patient before surgery that transplantation may not be able to

be done, and a "backup" patient is prepared so that the organ does not go unused.

Alcoholic cirrhosis. The most common cause of cirrhosis in the United States and the western hemisphere is ALD.

Therefore, patients with alcoholic cirrhosis represent the largest number of potential adult OLT recipients. Alcoholic

cirrhosis, however, has historically been a relative contraindication to OLT for several reasons: (1) the high risk of patient

noncompliance associated with the alcoholism, (2) other medical disorders associated with alcoholism, such as

cardiomyopathy, chronic pancreatitis, cerebral atrophy, and protein-calorie malnutrition, and (3) the generally worse

outcome in alcoholics compared with nonalcoholics (on the basis of early reports).[23] However, more recent reports

confirm a good prognosis when appropriate protocols for abstinence are strictly adhered to and adequate psychosocial

support systems are in place.[24]

The criteria used to determine whether to transplant the patient with ALD vary among transplant centers. Clearly, the

patient who is an active alcoholic is at very high risk for psychological morbidity and an unsuccessful outcome, and is not

usually considered a candidate. On the other hand, the patient who has demonstrated some period of sobriety is

considered by most transplant teams to be a potential candidate. Although the establishment of arbitrary waiting periods is

not supported by the medical literature, the minimal length of time that a patient must have been sober before being

considered for OLT ranges from 6 months to 2 years. A further step taken by many transplant centers to ensure the best

chance for successful outcome is the requirement that patients also have completed an alcohol treatment or rehabilitation

program. The reader is referred to Surgical Clinics of North America, Volume 3, Number 3, 1999, for a comprehensive

review of OLT for alcoholic liver disease.

Pretransplant issues including evaluation and medical management of the patient with ESLD are discussed in detail in the

Manual of Liver Transplant Medical Care, also available on Medscape.[25]

Evaluation of the appropriateness of a potential candidate for OLT is a complex process and involves a multidisciplinary

approach. The evaluation begins with a thorough patient history and physical examination, including a psychiatric and

psychosocial evaluation. Patients should be initially evaluated by a hepatologist, surgeon, social worker, and financial

counselor. The goals of the evaluation are to: (1) confirm the etiology of liver disease and determine the medical necessity

for and proper timing of surgery, (2) determine the technical feasibility of the procedure, (3) identify any precluding

extrahepatic disease, (4) determine physiologic and psychological suitability, (5) clarify any contraindications to

transplantation, (6) identify organ systems that may require optimization before transplantation, and (7) clarify any other

conditions that need to be addressed prior to transplantation. In addition, various specialists are often consulted to give

their impressions and recommendations regarding patient suitability. This process is complex and time consuming, and

from the patient and family perspectives, it is often physicallly and psychologicallly stressful.

Once considered an acceptable candidate for OLT, the patient may require considerable treatment for sequelae of ESLD.

Paracenteses and thoracenteses may be required for the control of ascites and pleural effusions, and antibiotics may be

needed for the prevention or treatment of infection. Sclerotherapy may be necessary to control variceal bleeding, and

transfusions with blood products may be necessary to optimize the preoperative coagulation status.

A careful past medical history should be elicited from any patient with chronic liver disease. Specifically, this history should

focus on:

prior neonatal or adult hepatitis or jaundice;

history of blood transfusions;

detailed history of alcohol intake, including social use and abuse, related legal problems, need for rehabilitation

program (eg, Alcoholics Anonymous), and date of last drink;

detailed history of drug or polysubstance abuse, including need for rehabilitation program, patient insight into


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problem, and date of last drug use;

presence of tattoos;

history of occupational exposure to blood, bodily fluids, or hepatotoxins such as carbon tetrachloride; and

family history of liver disease.

The potential OLT recipient should be screened for psychological and/or sociocultural issues that predict poor outcome.

The screening process begins with obtaining information from the physician who refers the patient to the transplant center.

A transplant psychiatrist, psychologist, or social worker assesses the patient to identify psychosocial risks and to

determine the need for interventions. The patient is evaluated for self-destructive behaviors, evidence of poor compliance

with medical treatment and the transplant evaluation itself, and any maladaptive personality traits or disorders. If any

necessary treatment is unsuccessful, the patient may be disqualified as a candidate. It is important to verify the history

presented by the patient with another reliable source, as the candidate may feel the need to "pass" the evaluation and may

not fully disclose information related to these issues. Screening may also shed light on family issues and needs so that

planning for interventions or services can begin early.

Evaluation of alcohol-dependent and drug-dependent patients is difficult. There is not universal agreement on how long a

patient should be abstinent from drugs and/or alcohol prior to OLT, but abstinence for 6 months is a commonly used

criterion. In addition, patients abstinent for less than 3 years should be carefully evaluated for the likelihood of maintaining

long-term abstinence. Patients with polysubstance abuse (alcohol and drugs or multiple drugs) are at higher risk of

returning to substance use than those who abuse only alcohol.

The physical examination of the patient with ESLD usually reveals the consequences of portal hypertension, portacaval

shunting, and wasting. Thus, blood pressure tends to be low despite a normal heart rate. The patient's weight may be

artificially normal or even elevated due to edema and ascites. Careful observation of the patient may, however, reveal

evidence of severe muscle wasting, notably in the arms, legs, and temporal areas. Further examination may reveal spider

angiomata, jaundice, and poor dentition. Typical skin findings are spider angiomas, palmar erythema, and clubbing.

The abdominal exam usually reveals hepatomegaly at the expense of the left lobe, with a hard, nodular liver, ascites, and

splenomegaly. In advanced cases, the liver may be shrunken and not palpable. Collateral abdominal circulation and even

frank caput medusae may be seen. Paradoxically, some patients may be morphologically obese, despite severe

synthetic.

The cardiopulmonary exam may be normal or reveal evidence of pleural effusions (hepatohydrothorax) that are more

common on the right side and in patients with significant ascites. In the absence of valvular heart disease, the cardiac

exam may reveal a high-flow murmur due to the hyperdynamic circulatory status, which is common in patients with

cirrhosis.

The neurologic exam may reveal asterixis, encephalopathy, or even frank somnolence or coma.

Diagnostic tests are individualized according to the patient's disease, age, and comorbid conditions. Because chronic liver

disease can affect all major organ systems, various laboratory and other diagnostic tests are done to evaluate the major

organ systems and identify any contraindications to OLT. Baseline laboratory testing should include:

complete blood count, prothrombin time (PT);

partial thromboplastin time (PTT);

electrolytes including calcium and phosphorous;

blood urea nitrogen;

creatinine;


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liver enzymes;

liver function tests;

HBV and HCV serologies;

cytomegalovirus (CMV) and EBV serologies;

antinuclear antibodies;

antimitochondrial antibodies;

anti-smooth muscle antibodies;

ferritin;

thyroid function tests;

fasting blood sugar;

urinalysis;

total protein, cholesterol, and triglyceride levels; and

drug and alcohol testing.

Finally, serologic tumor screening should include alpha-fetoprotein and carcinoembryonic antigen levels.

All patients should undergo ultrasonography with Doppler, chest x-ray, electrocardiogram, and PaO2 testing. Patients over

age 40 and/or with an abnormal cardiac exam should undergo echocardiography, and patients with risk factors for

coronary artery disease should undergo dobutamine echocardiography. Patients with a PaO2 < 70 mm Hg should undergo

pulmonary function testing and "bubble contrast" echocardiography to assess for right-to-left intrapulmonary shunting.

Upper or lower endoscopy are not routinely performed, and MRI or CT scans are not usually done unless the ultrasound

exam is suspicious for malignancy. Patients with PSC and ulcerative colitis should undergo colonoscopy with biopsy of

suspicious lesions.

Women should have a gynecologic exam and age-appropriate Pap smear and mammography. Prostate specific antigen

testing should be done in age-appropriate men.

The medical necessity for OLT is usually straightforward as determined by the patient's specific disease(s). Optimal

timing, however, is much less clear and is highly individualized, depending primarily on the hepatic and systemic sequelae

of end-stage renal disease.

The Childs-Turcotte-Pugh (CTP) classification is used to establish minimal listing criteria in the UNOS allocation algorithm.

The CTP classification ( ) reflects the severity (mild, moderate, or severe) of cirrhosis. A point score is calculated by

assigning 1 to 3 points for each of 5 parameters. Scores are summed to determine Childs class A, B, or C: Childs class A

indicates < 7 points, Childs class B indicates 7-10 points, and Childs class C indicates > 10 points. Under this allocation

system, a patient had to be classified as at least Childs class B in order to be listed for transplantation.

Table 2. Childs-Turcotte-Pugh Classification of Severity of Liver Disease

Variable 1 Point 2 Points 3 Points

Encephalopathy None Moderate Severe

Ascites None Slight Moderate

Albumin (mg/dL) > 3.5 2.8-3.5 < 2.8

PT (INR) prolonged < 4 4-6 > 6


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(sec)

Bilirubin (mg/dL)

PBC

Cirrhosis/primary

PSC

1-4 4-10 > 10

All other diseases < 2 2-3 > 3

UNOS applied CTP scores to design a status system for prioritizing liver allocation. Status 3 (CTP score 7-9) and status

2B (CTP score ≥ 10) patients met minimal listing criteria. Status 2A and status 1 patients were considered most critical

(usually in the intensive care unit [ICU]) and received higher priority than status 2B and status 3 patients. Within each

status, waiting time was used as the tiebreaker between 2 or more patients.

As the gap widened between the number of patients needing liver transplantation and the availability of cadaver donors,

consensus began to build on the need to use more discriminating criteria for prioritizing liver allocation. A new system,

MELD, that prioritizes liver allocation based on severity of liver failure was chosen. MELD incorporates measures of

bilirubin, INR (international normalized ratio for coagulation testing), and serum creatinine. It results in a score of 6-40, is

predictive of death within 3 months, and is modified for pediatric patients (Pediatric End-Stage Liver Disease [PELD]).

MELD went into effect in the United States on February 27, 2000. Compared with the CTP scoring system, the MELD and

PELD scoring systems allow more accurate assessment of liver disease severity and better prediction of patient risk of

dying while on the waiting list.

Procurement of the donor liver is most often performed in conjunction with removal of other organs. Therefore, multiple

surgical donor teams must coordinate their efforts to remove organs from 1 cadaver donor as quickly and effectively as

possible. The goals of liver procurement are to: (1) determine if the liver is unacceptable for transplantation, (2) perform a

technically perfect donor hepatectomy, (3) avoid warm ischemia of the organs, and (4) minimize the cold ischemic time of

the donor organs.

Suitability of the donor liver cannot be determined until the liver is visually inspected in the donor's abdomen by an

experienced liver transplant surgeon. Even then, the ultimate outcome of graft function will not be known for up to 48 hours

or longer after transplantation. Matching the size of the potential recipient with the donor is an important consideration in

liver transplantation. Though criteria vary; in general, the donor weight should be within a 50-lb range of the recipient's ideal

body weight,[26] or the variance in weights between recipient and donor should not exceed 20%.[27] A detailed description

of donor liver recovery can be found in the "Organ Procurement" chapter in ACS Surgery: Principles & Practice.[28]

Technical advancements in surgery have made it possible to transplant most patients, but some factors increase the

operative risk. For example, PVT, prior biliary bypass operations, multiple intra-abdominal procedures, and major arterial

anomalies increase technical difficulty. Evaluation of technical problems involves radiologic evaluation to detect conditions

that would complicate transplantation or require modification of standard surgical procedures.

The surgical procedures for liver transplantation differ depending on whether the native liver is totally or partially removed,

and whether a whole or partial organ is transplanted. Procedures employed include: standard OLT, HLT, auxiliary partial

liver transplantation (APLT), reduced-size OLT, split-liver OLT, and living-donor liver transplantation (LDLT). The vascular

anastomoses for the standard procedure for OLT are shown in Figure 1. For a detailed description of surgical techniques

for liver transplantation, the reader is referred to "Surgical Techniques in Liver Transplantation" in Primer on

Transplantation.[29]


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Vascular anastomoses for orthotopic liver transplantation.

There are 2 distinct phases of postoperative care of the OLT recipient: (1) the immediate postoperative or stabilization

phase, and (2) the transitional phase, after the need for intensive care but before discharge from the hospital. Optimal

patient outcomes are dependent on a coordinated and collaborative interdisciplinary approach among nurses, physicians,

and ancillary personnel. Posttransplant care of the OLT recipient is discussed in detail in the Manual of Liver Transplant

Medical Care, also available on Medscape.[25]

Basic to care of the OLT patient is a thorough understanding of normal liver function, the pathophysiology of acute and

chronic liver failure, and the clinical sequelae of liver disease -- specificalllly portal hypertension and its major physiologic

consequences of collateral vessel formation, ascites, splenomegaly, and encephalopathy. Critical to nursing assessment

of the OLT recipient is recognition of normal vs abnormal liver (graft) function and patient responses to a vast and complex

array of nursing and medical interventions. The following discussion of nursing care focuses on prevention and treatment

of complications that commonly occur after OLT.

During surgery, the patient is subjected to extreme physiologic stress as a result of prolonged general anesthesia and a

complex operative procedure. After surgery, on admission to the ICU, the patient may have significant edema from fluid

resuscitation and consequent third-spacing of fluids, and a multiplicity of tubes, catheters, and drains present. It is

imperative that the family be adequately prepared to see the patient for the first time after surgery. They will usuallly

require reassurance that what they will see is normal and not unusual or resulting from early complications. This

perspective is an important starting point for care of the OLT recipient.

The liver allograft sustains injury as a result of preservation and reperfusion upon implantation into the recipient and

restoration of blood flow. Insults related to preservation and reperfusion affect early graft function, and preservation injury

appears to increase the likelihood of graft rejection. The probability of preservation injury increases when the cold

ischemic time exceeds 24 hours. Mechanisms of reperfusion injury involve the sinusoidal endothelial cells of the liver.


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These cells die as a result of several potential factors: local release of reactive oxygen intermediates, tumor necrosis

factor-alpha, proteases, or increased intracellular calcium concentration.[30] On reperfusion, the Kupffer cells release

reactive oxygen intermediates and proinflammatory cytokines and chemokines that facilitate the inflammatory response.

Preservation and reperfusion injury may be exacerbated by primary graft nonfunction due to predisposing donor and/or

recipient factors. As more and more marginal and expanded donors are used in response to the donor shortage, the risk

of delayed function and PNFG is increased.

One of the lesser understood dilemmas of OLT is the phenomenon of the PNFG, the graft that despite all efforts by organ

recovery and transplant teams to ensure its viability, fails to function. In most cases, a PNFG will be clinically evident

almost immediately upon revascularization of the graft in the OR where the functioning liver graft should produce bile

immediately and coagulopathy should improve. If these do not occur, this is an early clue that there may be a problem.

Assessment of graft function is an immediate and ongoing responsibility of the critical care nurse.

The most sensitive laboratory indices of liver function are the coagulation factors, PT and PTT. Alteration in liver function is

reflected very early by prolonged coagulation times. The PT and PTT in the immediate postoperative period will vary,

depending on the preoperative levels and intraoperative events. What should occur, though, is a steady downward trend

toward normalcy in both the PT and PTT. If this does not occur, the clinician should suspect PNFG.

Hyperglycemia is another favorable sign in the immediate postoperative period, indicating that the liver is able to store

glycogen and convert it to glucose, and respond to the metabolic effects of corticosteroids. This may require short-term

insulin therapy and frequent serum glucose monitoring. Hypoglycemia, like hyperkalemia, indicates nonfunctional

hepatocytes and is an unfavorable sign.

The serum transaminases (aspartate aminotransferase, alanine aminotransferase) and phosphatases (alkaline

phosphatase, gamma glutaryl transpeptidase) and the serum bilirubin should show a progressive downward trend after

OLT. Recovery is associated with a prolonged period of cholestasis, which may last several months.

Finally, the clinical status of the patient provides an important and early clue to liver function. The importance of liver

function on other vital systems becomes evident in the setting of PNFG. Evaluation of mental status for the development

of encephalopathy is difficult because the patient has an endotracheal tube and is partially anesthetized. Failure of the

patient to gradually wake up may be the only neurologic manifestation of PNFG. Acute hepatorenal syndrome will

accompany PNFG, which leads to hypervolemia and pulmonary edema, manifested by elevated right and left heart filling

pressures, hypoxemia, failure to wean from mechanical ventilation, and peripheral edema. Another important sign is

correction of lactic acidosis. A functioning liver clears lactate rapidly, usually within 12 to 24 hours. The presence of a

noncorrecting or rising lactate should raise suspicion of PNFG.

The differential diagnoses for PNFG include recovery ischemia, hyperacute rejection, and other unknown causes. PNFG

is a life-threatening situation; the only treatment is immediate retransplantation, usually within 48 hours. From a

psychological perspective, this is devastating to the family (and patient if he or she is aware of the situation), who have

anticipated the safe return of their loved one to the ICU. Temporary support measures until the patient is retransplanted

include continued mechanical ventilation, ultrafiltration for management of fluid and electrolyte imbalances, and

supplementation of coagulation factors with fresh frozen plasma (FFP), cryoprecipitate, and platelets if necessary.

Historically, many OLT recipients were hypothermic to some degree, though this is much less commonplace today due to

shorter operative times and use of warming strategies in the OR. Contributing factors to hypothermia in the OLT recipient

include ambient temperature in the OR, wet surgical preparation procedures, preoperative and postoperative narcotics

and muscle relaxants, prolonged general anesthesia, prolonged exposure of the peritoneum and bowel to the

atmosphere, unwarmed IV fluids and surgical field irrigation solutions, and the cold preservation technique used in the

donor liver. The recognition and modification of these factors to the extent possible can prevent or limit the unwanted

physiologic consequences of severe hypothermia.

The physiologic consequences of hypothermia can contribute to an unstable course in the immediate postoperative

period. Severe hypothermia is associated with cardiac dysrhythmias, which can add to the usual state of cardiovascular

instability during this time. Although severe hypothermia is no longer the norm, moderate hypothermia is common and can

prolong anesthetic recovery, alter platelet function and clotting ability, shift the oxyhemoglobin dissociation curve to the left

-- causing metabolic alkalosis and hypokalemia, and increase systemic vascular resistance (SVR).


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Since the majority of adult OLT recipients have an indwelling pulmonary artery catheter, monitoring of the core temperature

is easily accomplished. The patient's thorax, hands, and feet should remain covered until rewarming is complete, and the

head should be covered in some fashion to prevent heat loss. This is difficult to accomplish when OR equipment is being

removed from the patient, ICU equipment is being attached to the patient, and when the anesthesiologist and nurse are

assessing the patient's condition after transport from the OR to the ICU. The tendency is to leave the patient's upper body

exposed to accomplish these tasks at a time when the body most needs to be covered. For this reason, and because

frequent assessments will be necessary during the first few hours after admission to the ICU, the use of radiant warming

devices and an overlying thin blanket layer are preferred over piling thick layers of blankets on the patient that must be

removed to perform the simplest task. IV fluids may also need to be warmed before infusion.

The patient's hemodynamic status is monitored continuously during the rewarming phase. Cardiovascular instability

(discussed in the section cardiovascular Instability below) will be exacerbated near the end of the rewarming phase as the

SVR decreases, resulting in vasodilation and relative hypovolemia. At this time, the volume of IV fluids required will

increase, and the flow rate of any continuous infusions of antihypertensive agents will need to be decreased. Anticipating

hypothermia and being prepared to intervene when the patient arrives from the OR is an important nursing priority.

There are 2 major causes of cardiovascular instability in the immediate postoperative period: (1) hypovolemia, and (2)

systemic arterial hypertension. Intensive cardiovascular assessment and monitoring are often the most important focus of

nursing care for the first 24-48 hours after surgery. Most adults have a pulmonary artery catheter for monitoring right and

left heart filling pressures, cardiac output, SVR, and pulmonary vascular resistance, which facilitates titration of fluids and

cardioactive and vasoactive drugs.

Patients with ESLD are usually hyperdynamic (high cardiac output and low SVR) before surgery. With progressive liver

disease, portal venous flow decreases and hepatic arterial flow increases compensatorily to maintain a constant liver

blood flow. This is reflected in an increased cardiac output. Another result of decreased portal blood flow is the

widespread development of splanchnic collateral vessels, which causes decreased resistance in the splanchnic vascular

bed. Decreased splanchnic resistance is manifested clinically as a decreased SVR. This altered hemodynamic profile

generally persists into at least the early postoperative period; therefore, it is important to use the patient as his or her own

control when assessing these hemodynamic parameters. Left-sided heart filling pressures are the most useful guide to

monitoring cardiovascular pharmacologic interventions.

Hypovolemia can result from a massive shift of intravascular fluid to the interstitial spaces (third-space loss), the

reaccumulation of ascites, and hemorrhage. The major factors contributing to third-space loss are the abdominal surgical

procedure, the physiologic stress of surgery, intraoperative fluid resuscitation, and hypoalbuminemia. Hypovolemia is

frequently exacerbated during rewarming of the hypothermic patient.

There is a confluence of lymphatic vessels in the area of the porta hepatis that is severed during the recipient

hepatectomy. Damage to these lymphatics can result in a significant accumulation of ascites fluid. Large volumes of

ascites may be removed by abdominal surgical drains. Abdominal drainage should be included when calculating fluid

balance. Resolution of postoperative ascites may take from several weeks to 3 months.

The most frequent technical complication requiring early reoperation is hemorrhage. Causes of early postoperative

hemorrhage include dilutional coagulopathy secondary to massive intraoperative blood transfusion, bleeding from

numerous raw peritoneal surfaces, and surgical technical errors such as a tie falling off of a vessel. Late postoperative

hemorrhage is most frequently attributed to complications from percutaneous liver biopsy and percutaneous biliary tract

procedures. The abdominal drains, commonly Jackson-Pratt drains (Figure 2), require frequent stripping to maintain their

patency for the assessment of the extent of abdominal ascites or the presence of blood or bile in the abdomen. These

drains are also a potential source of infection and as such must be handled in a manner to prevent the entry of potentially

pathogenic organisms into the abdomen.


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Abdominal drainage with Jackson-Pratt (JP) drains after orthotopic liver transplantation. JP1 is placed in the right

subphrenic space, JP2 is placed in the area of the porta hepatis, and JP3 is placed in the left subphrenic space.

Hypertension is a common phenomenon after OLT. It may be present for only a few days or weeks or may persist for

months after transplantation. The exact cause of hypertension in this setting is not well understood. However, proposed

etiologic factors include increased SVR resulting from catecholamine release during the stress response, manipulation of

the right adrenal gland during surgery, hypothermia, hypervolemia, renal insufficiency, and administration of calcineurin

inhibitors such as CsA or TAC. To determine the cause and institute the appropriate treatment, a hemodynamic profile (eg,

blood pressure, cardiac output, SVR, central venous pressure, and urine output) is necessary.

Virtually any metabolic imbalance can occur after OLT. This is not surprising, considering the magnitude of the physiologic

stress of surgery, fluid shifts, the multitude of pharmacologic agents administered, and multisystem complications. The

most common imbalances, however, are hypokalemia, hyperglycemia, hypomagnesemia, and metabolic alkalosis.

Hypokalemia is a temporary problem in the early postoperative period resulting from flushing of the preserved liver and

hypothermia that is easily corrected with IV potassium supplementation. Hypokalemia also occurs as a side effect of

potassium-wasting diuretic therapy, intracellular fluid shifts secondary to metabolic alkalosis, hypothermia, insulin therapy,

and corticosteroid therapy. In the late postoperative period, hypokalemia can result from excessive GI fluid loss (eg,

diarrhea). Rarely, if serum potassium is monitored regularly and supplementation given when indicated, is hypokalemia

from any cause significant enough to produce physical signs. Hyperkalemia in the early postoperative period can indicate

PNFG or vascular thrombosis with subsequent cell death and release of potassium.

The main causes of hyperglycemia have been previously discussed. Other causes include corticosteroid therapy, stress-

induced diabetes mellitus, and sepsis. Some patients develop diabetes mellitus as a permanent condition after OLT with

chronic corticosteroid therapy. Diabetes mellitus leads to increased morbidity and represents an added physiologic and

psychological burden to the patient. In the previously euglycemic patient, hyperglycemia may be one of the earliest signs

of sepsis, particularly in the immunosuppressed patient, who may not be capable of mounting the normal inflammatory

response.

Hypomagnesemia is another phenomenon after OLT. Many patients are hypomagnesemic from malnutrition before

transplantation, and the condition is exacerbated in the postoperative period. The exact nature of this problem is not

completely understood. However, contributing postoperative factors are thought to include diuretic therapy, effect of


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calcineurin inhibitors (CsA, TAC), and hypocalcemia that occurs as a result of the massive transfusion of stored blood

(rare). Unlike hypokalemia, the clinical manifestations of hypomagnesemia are frequently evident and include

neuromuscular irritability and sleeplessness. In extreme cases, seizures can occur. Routine monitoring of the serum

magnesium and supplementation with IV or oral magnesium sulfate as indicated will prevent these problems.

Metabolic alkalosis is the most common acid-base disturbance in the immediate postoperative period and is most

prominent during the first 24-48 hours after surgery. Precipitating factors include the large citrate load (from stored blood)

that is metabolized to bicarbonate, hypokalemia, diuretic therapy, and the administration of large volumes of FFP that is

deficient in chloride. Metabolic alkalosis can complicate weaning the patient from mechanical ventilation. The patient will

hypoventilate in response to the alkalosis and become hypercarbic. Generally, this problem resolves spontaneously as the

other factors are diminished. Intravenous hydrochloric acid by continuous infusion or acetazolamide, a carbonic anhydrase

inhibitor, can be administered to correct metabolic alkalosis.

The OLT recipient is at great risk for the development of pulmonary complications. First, the patient is subjected to a very

long surgical procedure in the supine position and a prolonged course of general anesthesia, both of which contribute to

atelectasis. Second, endotracheal intubation and mechanical ventilation are necessary for a variable length of time to

support ventilation and oxygenation during and after surgery. This predisposes the extremely immunosuppressed patient

to the development of pulmonary infections. Third, immobility for extended periods of time can be a problem after the long

and complex operation or in the unstable patient. A primary goal in the immediate postoperative period is to wean the

patient from mechanical ventilation so that the endotracheal tube can be removed and normal ventilation can be resumed.

Efforts to wean the patient from mechanical ventilation can be thwarted by paresis or paralysis of the right hemidiaphragm

(secondary to phrenic nerve damage as a result of retraction and dissection during surgery), decreased vital capacity

resulting from upper abdominal wall incisions, atelectasis, pleural effusion, and metabolic alkalosis.

Pulmonary compromise in the OLT recipient is classified as either ineffective ventilation or ineffective oxygenation. The 2

major factors that contribute to ineffective ventilation are damage to the right hemidiaphragm and ascites. During the

recipient hepatectomy phase of the surgical procedure, the right hemidiaphragm may be damaged due to difficult

dissection. There are no specific interventions for this problem, but fortunately, over time, this problem resolves

spontaneously. Ineffective ventilation is manifested by a decreased ventilation/perfusion ratio and an increased paCO2.

Ineffective oxygenation is a common problem with multiple causes: preexisting pulmonary shunting, atelectasis and

intrapulmonary shunting, pneumonia, pleural effusions, hypervolemia, immobility, and adult respiratory distress syndrome

related to intraoperative events and sepsis. Ineffective oxygenation is manifested by an increased intrapulmonary shunt

fraction, decreased paO2, and decreased SaO2. Frequent pulmonary assessment, evaluation of arterial blood gases, and

chest physical therapy are the mainstays of pulmonary care for the OLT recipient with ineffective oxygenation.

Pleural effusions are common. They are frequently confined to the right side and result from surgical procedure and the

presence of ascites. As previously stated, the diaphragm is easily injured during the recipient hepatectomy. Inflammation

from the injury and the translocation of intra-abdominal fluid into the pleural space contribute to the development of

effusions. Frequent assessment of the lungs for diminished sounds at the right base caused by a pleural effusion is

necessary. It is not uncommon during the recovery phase for an OLT recipient to accumulate effusions large enough to

require several thoracenteses or placement of a chest tube for drainage.

The most common pulmonary complications are infectious (bacterial, viral, fungal, protozoal) in nature.A variety of

bacterial infections can occur, usually earlier than infections from other types of organisms. Viral infections predominantly

originate from CMV. CMV pneumonia is diagnosed by bronchiole alveolar lavage and frequently occurs simultaneously

with CMV hepatitis in the highly immunosuppressed patient.

Renal Insufficiency

The potential for postoperative renal insufficiency in the OLT recipient is great. Patients have varying degrees of renal

insufficiency before surgery and are thus at greater risk for morbidity and mortality than the patient with normal renal

function. The preoperative serum creatinine level is an accurate predictor of poor survival in this group of patients.[31]

Intraoperative and postoperative factors that contribute to renal insufficiency include massive hemorrhage and

hypotension, postoperative hypovolemia, infection, graft failure, broad-spectrum antibacterial and antifungal therapy, and

calcineurin inhibitor therapy.

The serum creatinine is typically elevated to 1.5-2.5 mg/dL due to a progressive fall in the glomerular filtration rate. This is

largely associated with the use of calcineurin inhibitors and is exacerbated in the presence of diabetes and/or


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hypertension. Management of calcineurin inhibitor-associated nephrotoxicity includes calcineurin inhibitor dose reduction

and addition of MMF and sirolimus to the immunosuppressive regimen.

Calcineurin inhibitors can also cause renal tubular acidosis, associated with hypomagnesemia and hyperkalemia.

Hypomagnesemia, in turn, can lead to seizures, and hyperkalemia can lead to arrhythmias and/or cardiac arrest.

Management is by magnesium supplementation (hypomagnesemia) and low-potassium diet (hyperkalemia). Occasionally,

the addition of mineralocorticoids may be necessary.

Frequently, there are multiple simultaneous contributing factors. In the majority of patients, these factors cause a

short-term acute tubular necrosis that usually resolves within 3-4 weeks. During this time, supportive measures such as

hemofiltration or hemodialysis may be necessary. In 1 series, acute renal failure requiring hemodialysis was the only

statistically significant predictor of decreased patient survival.[32] Daily assessment of the serum creatinine level and

creatinine clearance in response to the above-mentioned factors is prudent. Regular monitoring of serum drug levels and

manipulation of antibiotic and immunosuppressant regimens is frequently necessitated.

Coagulopathy

Coagulopathy, to one degree or another, is a preexisting condition in most OLT recipients. Primary liver dysfunction and

splenomegaly with pancytopenia are the major preexisting contributing factors. Intraoperative hemostasis is complicated

by coagulopathy, frequently necessitating the transfusion of large volumes of blood, which can create further coagulopathy

via dilutional mechanisms. Thus, a vicious intraoperative cycle is established that can persist into the postoperative period.

Additional postoperative factors that can contribute to the development of coagulopathy include hypothermia,

disseminated intravascular coagulation, drug-related bone marrow toxicity, and graft failure. Coagulopathy in the early

postoperative period can be disastrous when one considers the major vascular anastomoses and the invasive monitoring

required for optimal assessment and treatment of the patient. Coagulopathy can also interfere with postoperative care by

contraindicating necessary procedures such as a liver biopsy.

Frequent assessment of coagulation times, clotting factor assays, serum fibrinogen, and degradation products of

fibrinolysis in the early postoperative period is imperative. A hypercoagulable state is common, so use of FFP is selective

to avoid vascular thrombosis in the perioperative period. Platelets and cryoprecipitate are less frequently required and

frequently avoided for the same reasons. As is true for any patient with a coagulopathy, care must be taken to prevent

trauma to the skin and mucous membranes.

Vascular complications include thrombosis and stenosis of the hepatic artery and/or portal vein. About 5% of OLT

recipients develop HAT. Half of these develop HAT early, usually within a week after implantation of the allograft. HAT is

more common in pediatric recipients with small vessels, in grafts with accessory vessels requiring surgical reconstruction,

in grafts that suffer severe ischemic injury, poor outflow, and insufficient inflow (eg, small recipient artery, median arcuate

ligament syndrome), or with certain technical factors (eg, intimal and/or anastomotic flaps). HAT is only rarely caused by a

hypercoagulable state. The presentation of HAT can vary from frank allograft failure, most common in the early

postoperative period, to a more insidious allograft dysfunction.

Acute HAT usually results in acute massive hepatic necrosis. The sudden onset of hepatic gangrene is manifested by

acute liver failure and sepsis with fever, hypotension, and acute renal and respiratory failure. On abdominal x-ray

examination, gas can often be seen in the liver. HAT is confirmed by Doppler ultrasound and/or arteriogram. Biliary

complications are common with HAT, and manifest clinically as sepsis of biliary origin, associated with intrahepatic biliary

strictures with or without discrete areas of hepatic necrosis (bilomas). Early HAT with liver failure can be managed with

thrombectomy, but frequently requires retransplantation.Late-onset HAT is insidious and may be seen as a delayed biliary

leak or multiple diffuse biliary strictures (the donor bile duct depends on the hepatic arterial flow for its blood supply) or

intermittent sepsis. Late-onset HAT is usually a less emergent situation than acute HAT because of the formation of

collateral vessels, and is managed with biliary dilations and biloma drainage when necessary, but may require

retransplantation. Hepatic artery stenosis can present as sudden HAT or have a more insidious course with obscure

allograft dysfunction. Hepatic artery stenosis is managed by either angioplasty or surgical revision, prior to development of

HAT.

PVT and stenosis are rarely seen (< 1%). PVT can present with liver failure in the immediate perioperative period or more

insidiously later on, with signs of portal hypertension (ie, ascites, gastropathy, or variceal hemorrhage). Management is by

thrombectomy or retransplantation in early cases, and by portosystemic shunting in the late cases. PVT is more common

in recipients with prior PVT, hypercoagulable states, hypotensive status, and recurrent cirrhosis with increased outflow


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resistance.

A variety of GI complications can occur after OLT. Expected complications that resolve spontaneously include ileus,

mild-to-moderate gastric outlet obstruction, and loss of appetite. Stress ulceration is anticipated and can be prevented by

administration of prophylactic H2 receptor blockers and antacids.

Malnutrition is a preoperative problem associated with ESLD and a postoperative complication. The stress of surgery, the

healing requirements of the body and other postoperative complications, mainly infection, contribute to increased

metabolic needs at a time when appetite and patient motivation may be poor. Laboratory nutritional assessment

parameters include serum albumin, serum transferrin, serum cholesterol, and urine urea nitrogen, which reflects the

patient's metabolic response to stress. Enteral and peripheral or central hyperalimentation are frequently necessary to

provide adequate calories and protein to maintain the patient in a state of positive nitrogen balance. Central

hyperalimentation is avoided if possible because of the increased incidence of fungal sepsis associated with this therapy

in the immunosuppressed patient.

An acute condition of the abdomen is an unexpected complication of OLT. Causes include small bowel obstruction, bowel

infarction, bowel perforation, peritonitis, pancreatitis, hemorrhage secondary to anastomotic leaks, and abdominal

abscess. Assessment for peritoneal signs of an acute condition of the abdomen -- sudden onset of ileus, nausea and/or

vomiting, abdominal tenderness, abdominal rigidity, and rebound tenderness -- is an important component of the

abdominal assessment of the OLT recipient. It is also important to note that recognition of this process may be delayed,

primarily because of the effects of corticosteroids, and thus, heightened awareness is necessary. With the possible

exception of pancreatitis, an acute abdominal condition is a surgical emergency. Nursing care includes preparation of the

patient for diagnostic procedures, surgery, and postoperative wound care, often involving complex management of

surgical tubes and drains.

In patients with a choledochojejunostomy (CBD anastomosed to the jejunum), bowel perforation can occur at the

jejunostomy site secondary to an anastomotic leak. Bowel perforation can also occur in other areas of the small bowel,

cecum, or colon as a result of denuded areas of serosa. Long-term corticosteroid therapy, which inhibits normal tissue

healing, is also a contributing factor to breakdown of anastomoses. Clinical manifestations of bowel perforation in the OLT

recipient include cloudy abdominal drainage, the presence of enteric organisms in the abdominal drainage, and wound or

systemic candida infection. Surgical intervention is necessary whenever a bowel perforation occurs at any site.

The preferred techniques for billiary anastomosis are choledochocholedochostomy (duct-to-duct anastomosis or CD-CD)

or Roux-en-Y choledochojejunostomy (duct-to-bowel anastomosis or CD-J), depending on anatomic factors, duct size

discrepancy, underlying native liver pathology, and surgeon preference. Billiary complications occur in up to 15% of cases

and have an associated mortality rate of 10%.[33] The range of complications depends on the age of the patient; stricture

and obstruction are more common in children.

Most complications occur within the first 3 months after transplantation; leaks occur during the first month and strictures

occur later. Most biliary leaks are due to anastomotic complications, but other causes include HAT, leaks from aberrant

ducts, or leaks from the surface of a reduced-size or spllit liver. The most common cause of billiary obstruction is also

anastomotic complication; other causes include hepatic artery stenosis or thrombosis, recurrent cancer or disease, and

ischemic injury.

The laboratory diagnosis of billiary complications depends on elevated billirubin gamma-glutamyltransferase and alkaline

phosphatase levels. The differential diagnosis includes sepsis, ischemic graft injury, and rejection.

Occasionally, neurologic complications occur in OLT recipients. These are more common in adults than in children. Most

neurologic complications are related to idiosyncratic central nervous system effects of or metabolic abnormalities caused

by immunosuppressive agents, most notably the calcineurin inhibitors. When toxic levels are reached, CsA and TAC may

produce a wide clinical spectrum of signs and symptoms, from tremor and acute confusion to status epilepticus.[34]

Calcineurin inhibitor-related neurotoxicity occurs in approximately 25% of liver transplant recipients.[35] These temporary,

dose-related side effects include impaired mentation or confusion, psychosis, dysphasia, mutism, cortical blindness,

extrapyramidal syndromes, quadriplegia, encephalopathy, seizures, and coma. Treatment includes consideration of

temporary discontinuation of CsA or TAC and identification of drugs that may increase immunosuppressive levels and

thereby trigger neurotoxicity: (1) for cyclosporine, cephalosporins, diltiazem, verapamil, and high-dose

methylprednisolone, and (2) for tacrolimus, erythromycin, danazol, and fluconazole.[34]


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Seizures may be aggravated by high-dose corticosteroids, hypomagnesemia, and hypertension. The differential diagnosis

for confusion includes encephalopathy due to graft failure, CsA toxicity, cryptococcal meningitis, abscess, graft

dysfunction, psychosis, sleep deprivation, cerebrovascular accident, and intracranial bleeding.

Infection is the major cause of morbidity and mortality after OLT. General factors that predispose the OLT recipient to

early infection are a debilitated preoperative state, preoperative derangement of the hepatic reticuloendothelial system,

abdominal surgery, prolonged operative time, hemodialysis, and GI and vascular complications. Pathophysiology and

treatment of opportunistic infection in the transplant recipient is described in detail in Chapter 4 of this book, Infection in

the Organ Transplant Recipient.

Early infections are primarily bacterial in origin. Assessment of the OLT recipient for signs of early infection is not

straightforward. As with any immunosuppressed patient, the signs of infection may be diminished or masked altogether.

Furthermore, there are many potential sites of infection that make the diagnosis both difficult and time consuming. Several

sites routinely become colonized with bacteria and fungi: abdominal drains, nasogastric tube, oral cavity (and sputum), and

wounds. Differentiating between colonization and true infection is important (and often difficult) to ensure accurate

treatment with antimicrobial agents. In addition to culture reports, the patient's clinical status must be taken into

consideration when making the diagnosis of infection. Failure to correctly differentiate between rejection and infection or

other conditions that cause elevation of the serum bilirubin, transaminases, and phosphatases, however, results in

overtreatment with corticosteroids, thereby increasing the risk of serious infection.

Opportunistic infections occur later and are primarily viral and fungal in origin, and occur as a result of long-term

immunosuppressive therapy. Viral infections are the most common infections in this patient population. The usual viral

pathogens are CMV, EBV, herpes simplex virus, and varicella. CMV, the most common offending agent, may present with

fever, malaise, leukopenia, hepatitis, esophagitis, enterocolitis, pneumonitis, or retinitis. Fungal infections in OLT

recipients frequently involve Candida sp (most common), Aspergillus, Cryptococcus, and Histoplasma, and are

associated with high mortality rates. Patients at high risk for fungal infections are often under heavy immunosuppression,

have a certain degree of allograft dysfunction, and are under heavy broad-spectrum antibiotic therapy. Aspergillus

infection often presents with respiratory symptoms; cryptococcal infection often presents with meningitis. Other

opportunistic agents include Pneumocystis carinii, Mycobacterium, Legionella, Nocardia, and Listeria.

Care of the OLT recipient is labor intensive in the immediate postoperative phase. Because of the need for extensive

invasive monitoring equipment and procedures for assessment and treatment, the patient comes in contact with numerous

members of the healthcare team, all of whom are potential vectors of pathogenic organisms. Adherence to infection

control standards is of paramount importance in preventing infection in this patient population. Unfortunately, this may

place the nurse in the position of "traffic controller" and watchdog for those who dismiss the importance of hand washing

as the most important infection control measure.

The most important consideration of graft survival is the ability to control rejection. The relatively short maximum cold

ischemic time of the liver precludes HLA typing and leukocyte cross-matching, though clinically these factors are not as

important in OLT as in other types of transplantation.

ABO matching between donor and recipient is the only prospective histocompatibility testing done for OLT. ABO matching

for OLT is shown in . The ideal situation is an ABO identical or nonidentical but compatible match, such as a blood group

O donor to a blood group A recipient. However, in emergent situations such as AFHF, PNFG, or acute vascular

thrombosis, ABO-incompatible matches may be used under specific protocols.[36] Survival rates associated with ABO

identical grafts are better than those for compatible, nonidentical grafts. A major complication associated with ABO

nonidentical OLT is hemolysis. Hemolysis results from a form of graft-vs-host response in which B lymphocytes in donor

lymphoid tissue produce antibodies to recipient ABO antigens. Hemolysis in this setting typically occurs between the fifth

and eighth postoperative day.The patient will usually initially develop a spiking fever. The reticulocyte count and serum

bilirubin level will be elevated, and the serum hemoglobin level will decrease. A direct Coombs test will also yield positive

results. Interventions for severe hemolysis may include aggressive IV hydration, diuretics, packed RBC transfusion,

plasmapheresis, and, rarely, splenectomy.

Table 3. ABO Matching for Liver Transplantation

ABO Type Identical ABO

Type

Compatible but

Nonidentical

Incompatible

ABO


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ABO Type Type

A

B

AB

O

A

B

AB

O

O

O

O, A, B

B, AB

A, AB

A, B, AB

Although the liver is not as antigenic as other solid organs, assessment for rejection of the transplanted liver is a major

focus of patient care. The liver has immune characteristics (ie, Kupffer cells, vascular and sinusoidal endothelial cells, and

portal dendritic and inflammatory cells) that logically should promote graft rejection. On the contrary, there is minimal

expression of class I HLA antigens on hepatocytes, which favors decreased antigenicity. It is also thought that donor

Kupffer cells may be replaced with host macrophages, which would promote graft acceptance.

Acute, accelerated, and chronic rejection occur after liver transplantation, but there is debate as to whether hyperacute

rejection occurs, even when there is a positive antidonor (anti-T lymphocyte) cross-match between the donor and

recipient. There are 2 possible explanations as to why hyperacute rejection does not occur. First, the large liver mass, via

the reticuloendothelial function of the Kupffer cells, is thought to be capable of sequestering cytotoxic antibodies formed

against the graft. The presence of a sinusoidal rather than a capillary system in the liver may allow for removal of antigen

by the Kupffer cells lining the sinusoids. Second, the cytotoxic antibody titer may be diluted sufficiently as a result of

intraoperative blood loss and volume exchange to inhibit the humoral immune response.

The focus of this chapter is on acute liver rejection because it occurs more frequently and because it can be both

prevented (presumably) and treated. It is therefore a primary consideration to the nurse caring for the OLT recipient. The

basic mechanism of acute liver rejection is that described as the cellular immune response in Chapter 2 of this book,

Immunologic Aspects of Transplantation. Sensitization of host T lymphocytes occurs when antigen-presenting cells carry

the antigenic markers to the peripheral lymphoid tissue. Circulating lymphocytes are also exposed to foreign antigen within

the graft, where Kupffer cells act as antigen-presenting cells.

Acute liver rejection occurs as early as 7 to 10 days after OLT. Clinical signs and symptoms include tachycardia, fever,

malaise, right upper quadrant and right flank tenderness or pain, hepatomegaly, and increased ascites accumulation. The

patient's mental status may also change and disorientation may be noted. The serum transaminase, phosphatase, and

bilirubin levels become elevated, but these are not sensitive indicators of rejection. Calcineurin inhibitor toxicity, HBV

reinfection, CMV hepatitis, and ischemia may cause similar elevations.

Diagnosis of acute rejection is made by liver biopsy. A working schema for grading acute liver allograft rejection is used to

grade the necro-inflammatory activity that is potentially amenable to therapeutic intervention.[37] Most acute rejection

episodes are mild and do not lead to clinically significant architectural sequelae.[38] Early histologic changes of acute

rejection are lymphocytic infiltration in the portal tracts beneath the endothelial lining of the sinusoids and the walls of the

central veins and bile ducts. The diagnosis in the early postoperative period is often clouded by bile duct damage, which

can occur as a result of recovery-related ischemic injury or damage caused by preservation solutions. For this reason, an

intraoperative biopsy is done for later comparison. Notably, the hepatocytes are not involved until rejection is moderately

advanced, because although central vein and bile duct epithelia are rich in class I and II major histocompatibility complex

antigens, hepatocytes are relatively lacking in these antigens.

Compared with other vascularized organ grafts, chronic liver allograft rejection is uncommon, most likely due to the unique

immunologic properties of the liver allograft, the regenerative capacity of the liver, and better recognition and control of

acute rejection. The incidence is approximately 1% to 3%.[36]

Chronic rejection involves progressive deterioration of graft function. Chronic rejection is thought to be caused by immune

humoral reactivity leading to tissue fibrosis. It may be exacerbated by factors such as reperfusion injury, CMV infection,

hyperlipidemia, diabetes, or hypertension.

Histologically, it is characterized by hepatic arteriolar thickening, loss of bile ductules, and hepatic fibrosis, resulting in

jaundice, loss of synthetic function, and portal hypertension.Chronic liver rejection was traditionally thought to indicate the

need for retransplantation. However, with the advent of newer, more powerful immunosuppression (eg, TAC, MMF, and

sirolimus), many of these cases can be successfully reversed.

After transplantation, patients are placed on immunosuppression to prevent acute and chronic rejection of the transplanted


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organ. The immunosuppressive agents used to treat acute rejection and nursing implications are discussed in detail in

Chapter 3 of this book, Immunosuppressive Therapies Used in Transplantation. A randomized study of sirolimus, a

relatively new immunosuppressive agent, in 222 primary liver allograft recipients recruited from 23 centers in Australia,

Europe, and North America, randomly assigned subjects before OLT to 1 of 2 treatment groups: (1) sirolimus, low-dose

TAC, and corticosteroids; n = 110; or (2) standard TAC and corticosteroids; n = 112.[39] Twelve-month patient and graft

survival in the sirolimus-TAC-corticosteroid group were significantly lower than in the TAC-corticosteroid group (patient

survival: 86.4 % vs 94.6%, respectively, P = .04; graft survival: 80.0% vs 91.1%, respectively, P = .02). Patients receiving

sirolimus had numerically greater rates of wound infection, sepsis, and thrombosis of major hepatic vessels, although only

the difference for wound infection achieved statistical significance. In contrast to these methods, Trotter and

colleagues[40] used sirolimus as the primary immunosuppressive agent. Sirolimus appeared to be safe when combined

with either TAC or CsA in a regimen aimed at withdrawing all corticosteroids by 2 weeks after transplantation. More

long-term data are needed on the role of sirolimus in OLT.

The focus of care of patients on immunosuppression is often on the side effects of these agents rather than on any actual

physical problems resulting from rejection. These drugs are usually used in combination to affect different immune

system activators and provide immunosuppressive synergy. In turn, this allows dose reductions in individual drugs over

time and minimizes side effects. Superiority of 1 regimen over another has not been demonstrated, and

immunosuppressive protocols are largely program-specific.

Familiarity with the immunosuppressive agents used in a particular program's protocol is critical, along with therapeutic

drug monitoring via serum levels and graft evaluation and monitoring for adverse drug reactions. However, regimens

should be flexible enough to accommodate individual patient characteristics, such as the degree of renal function and

age. Finally, even the best thought-out regimen is doomed to failure without patient compliance, since failure to comply

often results in organ rejection and failure.

The current challenge in the management of liver transplant recipients is maintaining health, well being, and quality of life in

long-term survivors. Problems encountered more long term after OLT are usually related to side effects of chronic

immunosuppressive therapy, disease recurrence, or chronic rejection. Improved long-term survival necessitates careful

screening for and management of long-term medical complications, including cardiovascular complications, malignancy,

bone disease, renal dysfunction, and disease recurrence.

The evolution of care of the liver transplant recipient is for the transplant surgeon to manage the patient in the immediate

postoperative period, and about 40% of the time to gradually transition that care to hepatologists and primary care

physicians.[41]Health maintenance includes screening for dyslipidemias, hypertension, malignancy (breast, colorectal,

cervical, prostate), diabetes mellitus, and thyroid disease. The reader is referred to 2 sources for detailed discussions of

long-term health risks and primary and secondary prevention: "Long-term Management of the Liver Transplant Patient", a

supplement to Liver Transplantation, [42] and "Refining Expectations in Transplantation: Managing Cardiovascular Risk," a

supplement to Transplantation.[43]

There have been numerous changes and advances in liver transplantation over the past decade. Three, however, deserve

special mention: the growth of adult-to-adult living donor transplantation, pegylated interferon therapy for recurrent HCV

infection, and changes in liver allocation policies and procedures. In addition, improvements have been made in

immunosuppressive strategies, particularly minimal immunosuppressive regimens and corticosteroid withdrawal. Two

major challenges face the field: (1) the growing disparity between the increasing number of patients seeking liver

transplantation and the plateau in the number of cadaver liver donors, and (2) management of long-term survivors.

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Cite this article: Liver Transplantation. Medscape. Mar 26, 2003.


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