**3.1 Preoperative evaluation and premedication**

The selection of appropriate and perfectly prepared recipient is the gold standard for the success of liver transplantation. Besides the complexity of the operation, most patients have an already disturbed physiology because of the hepatic disease, challenging the anesthesiologist (Table 1) (Findlay, 2002). Liver diseases strike all major organ systems leading to an unexpectedly chaotic scenario for the anesthesiologist, including hepatic failure, multiorgan dysfunction, encephalopathy, and severe metabolic disorders, and revealing the preoperative evaluation and premedication an essential part of the preparation of the patient. Besides, sepsis, metastatic malignancy, severe congestive heart failure, pulmonary hypertension and unresolved alcoholism are the contraindications for liver transplantations.

**Cardiovascular system:** Since the criteria for transplantation is expanded, the age limits has been extended to the older ages, thus bringing ischemic heart diseases as a major problem to be evaluated in the preoperative period (Steadman, 2004). Although coronary angiography is the gold standart for this assessment, considering the usage of radiographic contrast in a patient group with a high-risk of renal dysfunction precludes the usage of this technique; leading to other screening methods such as transthoracic echocardiography in combination with a stress test. Exercise tests are not suitable for end-stage liver disease patients, because they cannot complete the test adequately. Thus, pharmacologic stress tests; stress echocardiography or myocardial perfusion scan have to be used instead (Niemann, 2010). Dobutamine stress echocardiography (DSE) is the screening method in many centers; including the advantage of diagnosing pulmonary hypertension and valvular heart disease (Niemann, 2010; Steadman, 2004). Preoperative assessment should include echocardiography in order to determine the baseline cardiac function and pulmonary artery pressures (Findlay, 2002). In alcoholic liver disease, amyloidosis, hemochromatosis and Wilson's disease nonischemic cardiomyopathy may be seen. However hypertrophic cardiomyopathy is rarely seen, it may cause dynamic left ventricule outflow tract obstruction during liver transplantation (Aniskevich et al, 2007). Most of the end-stage liver disease patients have a hyperdynamic state characterised by an increased cardiac output and arteriolar vasodilatation (Glauser et al, 1990). Portopulmonary hypertension may be found in these patients. Severe


Table 1. Patophysiologic changes related to liver failure (Findlay, 2002; Ozier & Klinck, 2008)

• High cardiac output, • Low resistance,

size,

• Pleural effusion;

• Hypoxia • Restrictive pattern (ascites),

• Increased cardiac index and left atrial

• Mild left ventricular hypertrophy and ischemic heart disease; clinical cardiomyopathy (especially alcohol, amyloid, Wilson's hemochromatosis);

(especially cystic fibrosis, alpha-1 anti-

• Decreased and defective synthesis of Vit K dependent clotting factors, • Trombocytopenia (hypersplenism or

• Autonomic neuropathy (mild in cirrhosis, moderate in amyloid)

• Flow-related or anatomical intrapulmonary shunting (hepatopulmonary syndrome); • Non-cardiogenic pulmonary edema (fulminant hepatic failure); • Obstructive airways disease

trypsin deficiency); • Interstitial lung disease (primary

marrow depression), • Platelet dysfunction; • Low grade DIC and/or hyperfibrinolysis

biliary cirrhosis)

**System Patophysiologic changes related to liver failure** 

• Portopulmonary Hypertension

• Coagulopathy

• Anemia

failure)

sepsis;

• Hyponatremia • Hypomagnesemia, • Hyperkalemia, • Hypokalemia, and/or metabolic acidosis and hypoglycemia

• Hepatic encephalopathy • Cerebral edema (fulminant

• Hepatorenal Syndrome (prerenal failure from splanchnic 'steal'); • Acute tubular necrosis from

• Tacrolimus/cyclosporinrelated renal impairment; renal tubular acidosis

Table 1. Patophysiologic changes related to liver failure (Findlay, 2002; Ozier & Klinck, 2008)

• Hyperdynamic Circulation

**Cardiovascular** 

**Respiratory** 

**Hematologic** 

**Central Nervous** 

**Renal System, Electrolyte and Metabolic disorders**

**System** 

portopulmonary hypertension is associated with increased perioperative mortality and right heart failure (Krowka et al, 2000; Ramsay et al, 2000). For detecting preoperative portopulmonary hypertension, transthoracic echocardiography may be reliable enough in experienced hands, but echocardiography should be reperformed.

**Respiratory system:** Respiratory complications seen in liver disease include restrictive lung disease, intrapulmonary shunts, pulmonary hypertension and ventilation-perfusion abnormalities. Hypoxemia is often related to the restrictive lung disease caused by ascites and/or pleural effusions, frequently responding to fluid removal. However, hypoxia may occur in the absence of ascites or intrinsic pulmonary disease, then this is called hepatopulmonary syndrome; contributing to shunting, ventilation-perfusion mismatch and/or diffusion defects. The presence of pulmonary hypertension responding to vasodilators is not a contraindication for transplantation. Pulmonary hypertension may improve, persist or develop following transplantation (Steadman, 2004).

**Hematological system:** In addition to the routine blood tests; coagulation tests and arterial blood gases should also be obtained (Findlay, 2002). In the normal hemostasis, liver is important for the production of prothrombin, fibrinogen, factors V, VII, IX and X (except von Williebrand factor-synthesized in endothelial cells), sythesis of antithrombotic modulating factors (protein S, protein C and antithrombin III) and components of fibrinolytic system (plaminogen and α2-antiplasmin); also the clearance of activated coagulation factors. As the liver function is impaired, this natural balance between coagulation and its inhibition is impaired, whereas the balance between the fibrin polymerization and fibrinolysis is also disturbed; which occurs due to the decreased production of antiplasmin and inadequate clearance of tissue plasminogen activators, (Hannaman&Hevesi, 2011). All the coagulation factors are decreased, except fibrinogen and factor VIII. Besides, Fitzgerald factor, alpha-1 antitrypsin, alpha-2 macroglobulin, antithrombin-III and plasminogen levels are all decreased. Fibrin degradation products are positive in one third of the patients. Thrombocytopenia occurs in 70% of the patients, often complicated with the functional derangement of the platelets. For the best approach to treat coagulopathic disorders, defects must be identified in laboratory screening tests to predict bleeding risk in recipients, but the liver diseases have complicated effects on the balance between prohemostatic and antihemostatic mechanisms. Prothrombin time (PT), the activated partial thromboplastin time (APTT) and platelet count shows the defect in procoagulant functions. Unfortunately, defects in inhibitory pathways are less clear. The net effect of instability of these systems is unpredictable and administration of fresh frozen plasma (FFP), platelets and other blood products before the surgery should be reconsidered. There is a correlation between the severity of preoperative coagulopathy and intraoperative requirement for blood and blood products; as the severity increases, requirements are increased. Chronic disease anemia, malnutrition and bleeding is also common in recipients. In patients with the coagulation disorders intramuscular injections should be avoided.

**Central nervous system:** In advanced liver diseases, hepatic encephalopathy within a range of mild stupor, deep coma and unresponsiveness, is often seen. Diuretic therapy, gastrointestinal bleeding, infections and advancement in liver disease worsen encephalopathy. In order to exclude a preexisting organic disease mimicing hepatic encephalopathy, EEG, stimulated potential tests and computed tomography are recommended to be performed. Any organic disease, that contributes to the changes in cerebral functions, is a contraindication for liver transplantation. Cerebral edema occurs in 50% of the patients with acute fulminant hepatitis. Cortical atrophy and non-specific changes are also seen at variable degrees in patients with chronic liver disease. Chronic liver disease is rarely associated with cerebral edema, but hepatic clearance failure leads to accumulation of toxins and alterations in endogenous transmitters, messengers such as γ-amino butyric acid (GABA), glutamate and nitric oxide. In preencephalopathic patients benzodiazepines should be avoided. In fulminant liver failure with Grade III-IV encephalopathy intracranial pressure monitoring may be required in order to maintain cerebral perfusion pressure >60 mmHg (Ozier&Klink, 2008). A severe coagulopathy may result in intracranial hemorrhage.

**Renal system:** The most common cause of renal failure associated with hepatic failure is hepatorenal syndrome, which is characterized by the absence of primary renal disease, proteinuria, hypovolemia and hemodynamic cases of renal hypoperfusion. Treatment with vasoconstrictors improving splanchnic vasodilation, decreasing endogenous vasoconstrictors leading to an improvement in renal blood flow is often successful (Duvoux, 2002; Gines, 2004; Wong, 2004). Contrast for diagnostic procedures and nephrotoxic agents should be avoided in these patients. Even a less advanced renal disease deserves management because it may also worsen the posttransplant period (Davis, 2002).

**Gastrointestinal system:** Esophageal varices, portal hypertension, ascites are frequently seen in patients with end-stage liver-disease. This complex state also includes delayed gastric emptying which contributes to a major problem especially during the induction of the anesthesia, thus premedications should include "aspiration" prophylaxis with ranitidine, metoclopramide, and particulate-free antacid.

**Endocrine system:** In liver diseases it is widely known that the carbonhydrate and protein metabolism is impaired, and glucose intolarence and insulin resistance occur. Serum insulin level is increased both because of the hypersecretion and decreased clearance. In addition to this, in acute fulminant hepatitis, depletion of glycogen stores, decreased gluconeogenesis and other humoral changes may result in a severe hypoglycemia. In advanced liver diseases, severe reductions in albumin levels may also be seen (<2gr).

**Drug metabolism:** All the plasma proteins, especially albumin which mainly provides plasma oncotic pressure, are produced in liver, except gama-globulin. The decrease in albumin levels (<2gr) results in intra- and extravascular volume changes, leading to an increase in distribution volume of drugs (e.g. neuromuscular blocking agents). Also, the duration of action of some anesthetic agents (such as opioids) are prolonged because of the increased volume of distribution and decreased metabolism. End-stage liver disease patients may be resistant to some drugs due to increased binding to globulin. Thus, initial dosages of the drugs are increased; on the other hand, because of the decreased levels of albumin, the unbound fraction of the drugs is increased; which leads to increased effectivity and duration of action of these drugs.

**Premedication** is usually administered unless the patient has an advanced hepatic encephalopathy. Oral diazepam 5-10 mg, lorazepam 2-3 mg can be used for adult patients, whereas 0.1-0.2 mg/kg of diazepam can be used orally for pediatric group of patients. Intramuscular injections should be avoided in patients with coagulopathy. Low dose midazolam (1-2 mg/kg) has become a routine before induction in the anesthetic practice.

All patients should be considered to have full stomach; H2 receptor blockers and particulate-free antacids can be used preoperatively.
