Chapter 34: Anesthesia for Patients with Liver Disease

The prevalence of liver disease is increasing. Cirrhosis, the terminal pathology of most liver diseases, has a general population incidence as high as 5% in some autopsy series. It is a major cause of death in men in their fourth and fifth decades of life, and mortality rates are increasing. Ten percent of the patients with liver disease undergo operative procedures during the final 2 years of their lives. The liver has remarkable functional reserve, and thus overt manifestations of hepatic disease are often absent until extensive damage has occurred. When patients with little hepatic reserve come to the operating room, effects from anesthesia and the surgical procedure can precipitate hepatic decompensation and frank hepatic failure.

The hemostatic changes that occur with liver disease may cause hypercoagulation and thrombosis, as well as an increased risk of bleeding. The causes of excessive bleeding primarily involve thrombocytopenia, endothelial dysfunction, portal hypertension, kidney failure, and sepsis (see Chapters 31 and 51). Clot breakdown may be enhanced by an imbalance of the fibrinolytic system.

Chronic liver disease is characterized by the impaired synthesis of coagulation factors, resulting in prolongation of the prothrombin time (PT) and international normalized ratio (INR) (Table 34–1). The INR was designed to monitor the anticoagulant effect of warfarin, not the anticoagulant effect of liver dysfunction. In liver dysfunction, the anticoagulant factors (protein C, antithrombin, and tissue factor pathway inhibitor) are also reduced and may balance out any effect of a prolonged PT. This may be confirmed by assessing thrombin generation in the presence of endothelial-produced thrombomodulin. Adequate thrombin production requires an adequate number of functioning platelets. If the platelet count is greater than 60,000/μL, coagulation may well be normal in a patient with severe cirrhosis. In fact, more recently it has been shown that an increased von Willebrand factor (vWF) in liver disease may result in activated platelets allowing normal or increased coagulation despite a much lower platelet count. It is important to use point-of-care global viscoelastic coagulation testing to fully understand the state of coagulation (see later discussion).

Cirrhotic patients will typically have hyperfibrinolysis. However, individual laboratory tests may not give a true picture of the state of fibrinolysis. Thromboelastography (TEG), rotational thromboelastometry (ROTEM), and Sonoclot viscoelastic coagulation testing technologies are the optimal methods of demonstrating the global state of the coagulation system at a specific moment in time in any patient with liver disease (see Chapter 51).

ACUTE HEPATITIS

Acute hepatitis is usually the result of a viral infection, drug reaction, or exposure to a hepatotoxin. The illness represents acute hepatocellular injury with a variable degree of cellular necrosis. Clinical manifestations depend on the severity of the inflammatory reaction and on the extent of necrosis. Mild inflammatory reactions may present merely as asymptomatic elevations in the serum transaminases, whereas massive hepatic necrosis presents as acute fulminant hepatic failure.

Viral Hepatitis

Viral hepatitis is most commonly due to hepatitis A, B, or C viral infection. At least two other hepatitis viruses have also been identified: hepatitis D (delta virus) and hepatitis E (enteric non-A, non-B). Hepatitis types A and E are transmitted by the fecal–oral route, whereas hepatitis types B and C are transmitted primarily percutaneously and by contact with body fluids. Hepatitis D is unique in that it may be transmitted by either route and requires the presence of hepatitis B virus in the host to be infective. Other viruses may also cause hepatitis, including Epstein–Barr, herpes simplex, cytomegalovirus, and coxsackieviruses.

Patients with viral hepatitis often have a 1- to 2-week mild prodromal illness (fatigue, malaise, low-grade fever, or nausea and vomiting) that may or may not be followed by jaundice. The jaundice typically lasts 2 to 12 weeks, but complete recovery, as evidenced by serum transaminase measurements, usually takes 4 months. Serological testing is necessary to determine the causative viral agent. The clinical course tends to be more complicated and prolonged with hepatitis B and C viruses relative to other types of viral hepatitis. Cholestasis (see later discussion) may be a major manifestation. Rarely, fulminant hepatic failure (massive hepatic necrosis) can develop.

The incidence of chronic active hepatitis is 3% to 10% following infection with hepatitis B virus and at least 50% following infection with hepatitis C virus. A small percentage of patients (mainly immunosuppressed patients and those on long-term hemodialysis regimens) become asymptomatic infectious carriers following infection with hepatitis B virus, and up to 30% of these patients remain infectious with the hepatitis B surface antigen (HBsAg) persisting in their blood. Most patients with chronic hepatitis C infection seem to have very low, intermittent, or absent circulating viral particles and are therefore not highly infective. Approximately 0.5% to 1% of patients with hepatitis C infection become asymptomatic infectious carriers, and infectivity correlates with the detection of hepatitis C viral RNA in peripheral blood. Such infectious carriers pose a major health hazard to operating room personnel.

In addition to “universal precautions” for avoiding direct contact with blood and secretions (gloves, mask, protective eyewear, and not recapping needles), immunization of health care personnel is highly effective against hepatitis B infection. A vaccine for hepatitis C is not available; moreover, unlike hepatitis B infection, hepatitis C infection does not seem to confer immunity to subsequent exposure. Postexposure prophylaxis with hyperimmune globulin is effective for hepatitis B, but not hepatitis C. Effective therapies now exist for hepatitis C, but continued hepatocellular carcinoma surveillance remains important for these patients.

Drug-Induced Hepatitis

Drug-induced hepatitis (Table 34–2) can result from direct, dose-dependent toxicity of a drug or drug metabolite, an idiosyncratic drug reaction, or a combination of these two causes. The clinical course often resembles viral hepatitis, making diagnosis difficult. Alcoholic hepatitis is probably the most common form of drug-induced hepatitis, but the etiology may not be obvious from the history. Chronic alcohol ingestion can also result in hepatomegaly from fatty infiltration of the liver, which reflects impaired fatty acid oxidation, increased uptake and esterification of fatty acids, and diminished lipoprotein synthesis and secretion. Acetaminophen ingestion of 25 g or more usually results in fatal fulminant hepatotoxicity. A few drugs, such as chlorpromazine and oral contraceptives, may cause cholestatic-type reactions (see later discussion). Ingestion of potent hepatotoxins, such as carbon tetrachloride and certain species of mushrooms (Amanita, Galerina), also may result in fatal hepatotoxicity.

Because of increased perioperative risk, patients with acute hepatitis should have elective surgery postponed until the illness has resolved, as indicated by the normalization of liver tests. In addition, acute alcohol toxicity greatly complicates anesthetic management, and acute alcohol withdrawal during the perioperative period may be associated with a mortality rate as high as 50%. Only emergent surgery should be considered for patients presenting in acute alcohol withdrawal. Patients with hepatitis are at risk of deterioration of hepatic function and the development of complications from hepatic failure, such as encephalopathy, coagulopathy, or hepatorenal syndrome.

Laboratory evaluation of the patient with hepatitis should include blood urea nitrogen, serum electrolytes, creatinine, glucose, transaminases, bilirubin, alkaline phosphatase, albumin, platelet count, and PT. Serum should also be checked for HBsAg whenever possible. A blood alcohol level is useful if the history or physical examination is compatible with ethanol intoxication. Hypokalemia and metabolic alkalosis are not uncommon and are usually due to vomiting. Concomitant hypomagnesemia may be present in chronic alcoholics and predisposes to cardiac arrhythmias. The elevation in serum transaminases does not necessarily correlate with the amount of hepatic necrosis. The serum alanine aminotransferase (ALT) is generally higher than the serum aspartate aminotransferase (AST), except in alcoholic hepatitis, where the reverse occurs. Bilirubin and alkaline phosphatase are usually only moderately elevated, except with the cholestatic variant of hepatitis. The PT is the best indicator of hepatic synthetic function. Persistent prolongation of longer than 3 s (INR ≥1.5) following administration of vitamin K is indicative of severe hepatic dysfunction. Hypoglycemia is not uncommon. Hypoalbuminemia is usually not present except in protracted cases, with severe malnutrition, or when chronic liver disease is present.

If a patient with acute hepatitis must undergo an emergent operation, the preanesthetic evaluation should focus on determining the cause and the degree of hepatic impairment. Information should be obtained regarding recent drug exposures, including alcohol intake, intravenous drug use, recent transfusions, and prior anesthetics. The presence of nausea or vomiting should be noted, and, if present, dehydration and electrolyte abnormalities should be anticipated and corrected. Changes in mental status may indicate severe hepatic impairment. Inappropriate behavior or obtundation in alcoholic patients may be signs of acute intoxication, whereas tremulousness, irritability, tachycardia, and hypertension usually reflect withdrawal. Fresh frozen plasma may be necessary to correct coagulopathy. Premedication is generally not given in patients with advanced liver disease. However, benzodiazepines and thiamine are indicated in alcoholic patients with, or at risk for, acute alcohol withdrawal; nevertheless, benzodiazepines must be administered cautiously, as they may precipitate hepatic coma in an encephalopathic patient. This may be reversed in some patients with flumazenil.

Intraoperative Considerations

The goal of intraoperative management is to preserve existing hepatic function. Some patients with viral hepatitis may exhibit increased central nervous system sensitivity to anesthetics, whereas alcoholic patients will often display cross-tolerance to both intravenous and volatile anesthetics. Alcoholic patients also require close cardiovascular monitoring because the cardiac depressant effects of alcohol are additive to those of anesthetics; moreover, alcoholic cardiomyopathy may be present in alcoholic patients.

Inhalation anesthetics are generally preferable to intravenous agents because most of the latter are dependent on the liver for metabolism, elimination, or both. Standard induction doses of intravenous induction agents can generally be used because their action is terminated by redistribution rather than metabolism or excretion. A prolonged duration of action, however, may be encountered with large or repeated doses of intravenous agents, particularly opioids. Isoflurane and sevoflurane are the volatile agents of choice for patient with significant liver disease because they preserve hepatic blood flow and oxygen delivery. Factors known to reduce hepatic blood flow, such as hypotension, excessive sympathetic activation, and high mean airway pressures during controlled ventilation, should be avoided. Regional anesthesia, including major conduction blockade, may be employed in the absence of coagulopathy, provided hypotension is avoided.

CHRONIC HEPATITIS

Chronic hepatitis is defined as persistent hepatic inflammation for longer than 6 months, as evidenced by elevated serum aminotransferases. Patients can usually be classified as having one of three distinct syndromes based on a liver biopsy: chronic persistent hepatitis, chronic lobular hepatitis, or chronic active hepatitis. Patients with chronic active hepatitis have chronic hepatic inflammation with destruction of normal cellular architecture “piecemeal necrosis” on the biopsy. Evidence of cirrhosis is either present initially or eventually develops in 20% to 50% of patients. Although chronic active hepatitis seems to have many causes, it occurs most commonly as a sequela of hepatitis B or hepatitis C. Other causes include medications (methyldopa, isoniazid, and nitrofurantoin) and autoimmune disorders. Both immunological factors and a genetic predisposition may be responsible in most cases. Patients usually present with a history of fatigue and recurrent jaundice; extrahepatic manifestations, such as arthritis and serositis, are not uncommon. Manifestations of cirrhosis eventually predominate in patients with progressive disease. In evaluating patients for chronic hepatitis, laboratory test results may show only a mild elevation in serum aminotransferase activity and often correlate poorly with disease severity. Patients without chronic hepatitis B or C infection usually have a favorable response to immunosuppressants and are treated with long-term corticosteroid therapy with or without azathioprine.

Anesthetic Management

Patients with chronic persistent or chronic lobular hepatitis should be treated similarly to those with acute hepatitis. In contrast, those with chronic active hepatitis should be assumed to already have cirrhosis and should be treated accordingly (as discussed next). Patients with autoimmune chronic active hepatitis may also present with problems related to other autoimmune manifestations (such as diabetes or thyroiditis) or to the long-term corticosteroid therapy that they have likely received.

Liver cirrhosis refers to the damaging effects to the liver of inflammation, hepatocellular injury, and the resulting fibrosis and regeneration of hepatocytes. Cirrhosis is a progressive disease that eventually results in hepatic failure. The most common cause of cirrhosis in the United States was chronic alcohol abuse, but that has now been overtaken by nonalcoholic steatohepatitis accompanying the massive increase in morbid obesity prevalence. Other causes include chronic active hepatitis (postnecrotic cirrhosis), chronic biliary inflammation or obstruction (primary biliary cirrhosis, sclerosing cholangitis), chronic right-sided congestive heart failure (cardiac cirrhosis), autoimmune hepatitis, hemochromatosis, Wilson disease, α₁-antitrypsin deficiency, and cryptogenic cirrhosis. Regardless of the cause, hepatocyte necrosis is followed by fibrosis and nodular regeneration. Distortion of the liver’s normal cellular and vascular architecture obstructs portal venous flow and leads to portal hypertension and varices. Impairment of the liver’s normal synthetic and other diverse metabolic functions, along with widespread endothelial damage from toxins not cleared by the liver, may cause multisystem dysfunction.

Clinically, signs and symptoms often do not correlate with disease severity. Manifestations are typically absent initially, but jaundice and ascites eventually develop in most patients. Other signs include spider angiomas, palmar erythema, gynecomastia, and splenomegaly. Moreover, cirrhosis is generally associated with the development of three major complications: (1) variceal hemorrhage from portal hypertension, (2) intractable fluid retention in the form of ascites and the hepatorenal syndrome, and (3) hepatic encephalopathy or coma. Approximately 10% of patients with cirrhosis also develop at least one episode of spontaneous bacterial peritonitis, and some patients eventually develop hepatocellular carcinoma.

A few diseases can produce hepatic fibrosis without hepatocellular necrosis or nodular regeneration, resulting in portal hypertension and its associated complications with hepatocellular function often preserved. These disorders include schistosomiasis, idiopathic portal fibrosis (Banti syndrome), and congenital hepatic fibrosis. Obstruction of the hepatic veins or inferior vena cava (Budd–Chiari syndrome) can also cause portal hypertension. The latter may be the result of venous thrombosis (hypercoagulable state), a tumor thrombus (eg, renal carcinoma), or occlusive disease of the sublobular hepatic veins.

Preoperative Considerations

The detrimental effects of anesthesia and surgery on hepatic blood flow are discussed later in this section. Patients with cirrhosis are at increased risk of deterioration of liver function because of limited functional reserve. Successful anesthetic management of these patients is dependent on recognizing the multisystem nature of cirrhosis (Table 34–3) and controlling or preventing its complications.

A. Gastrointestinal Manifestations

Portal hypertension leads to the development of extensive portosystemic venous collateral channels. Four major collateral sites are generally recognized: gastroesophageal, hemorrhoidal, periumbilical, and retroperitoneal. Portal hypertension is often apparent preoperatively, as evidenced by dilated abdominal wall veins (caput medusae). Massive bleeding from gastroesophageal varices is a major cause of morbidity and mortality in patients with liver disease, and, in addition to the effects of acute blood loss, the absorbed nitrogen load from the breakdown of blood in the gastrointestinal tract can precipitate hepatic encephalopathy.

The treatment of variceal bleeding is primarily supportive, but frequently involves endoscopic procedures for identification of the bleeding site(s) and therapeutic maneuvers, such as injection sclerosis of varices, monopolar and bipolar electrocoagulation, or application of hemoclips or bands. In addition to the risks posed by a patient who is physiologically fragile and acutely hypovolemic and hypotensive, anesthesia for such endoscopic procedures frequently involves the additional challenges of an encephalopathic and uncooperative patient and a stomach full of food and blood. Endoscopic unipolar electrocautery may adversely affect implanted cardiac pacing and defibrillator devices.

Blood loss should be replaced with intravenous fluids and blood products. Nonoperative treatment includes vasopressin, somatostatin, propranolol, and balloon tamponade with a Sengstaken–Blakemore tube. Vasopressin, somatostatin, and propranolol reduce the rate of blood loss. High doses of vasopressin can result in congestive heart failure or myocardial ischemia; concomitant infusion of intravenous nitroglycerin may reduce the likelihood of these complications and bleeding. Placement of a percutaneous transjugular intrahepatic portosystemic shunt (TIPS) can reduce portal hypertension and subsequent bleeding, but may increase the incidence of encephalopathy. When the bleeding fails to stop or recurs, emergency surgery may be indicated. Perioperative risk correlates with degree of hepatic impairment, based on clinical and laboratory findings. Child’s classification for evaluating hepatic reserve is shown in Table 34–4. Shunting procedures are generally performed on low-risk patients, whereas ablative surgery, esophageal transection, and gastric devascularization are reserved for high-risk patients.

B. Hematologic Manifestations

Anemia, thrombocytopenia, and, less commonly, leukopenia may be present. The cause of the anemia is usually multifactorial and includes blood loss, increased red blood cell destruction, bone marrow suppression, and nutritional deficiencies. Congestive splenomegaly secondary to portal hypertension is largely responsible for the thrombocytopenia and leukopenia. Coagulation factor deficiencies arise as a result of decreased hepatic synthesis. Enhanced fibrinolysis secondary to decreased clearance of activators of the fibrinolytic system may also contribute to the coagulopathy.

The need for preoperative blood transfusions should be balanced against the obligatory increase in nitrogen load. Protein breakdown from excessive blood transfusions can precipitate encephalopathy. Nevertheless, coagulopathy should be corrected before surgery. Clotting factors should be replaced with appropriate blood products, such as fresh frozen plasma and cryoprecipitate. Platelet transfusions should be considered immediately prior to surgery for platelet counts less than 75,000/μL. Assessment of integrity of the coagulation system by viscoelastic technology will provide specific management information.

C. Circulatory Manifestations

End-stage liver disease, and in particular, cirrhosis of the liver may be associated with disorders of all major organ systems (Tables 34–3 and 34–5). Cardiovascular changes observed in cirrhotic patients are usually those of a hyperdynamic circulation, although clinically significant cirrhotic cardiomyopathy is often present and not recognized (Table 34–6). There may be a reduced cardiac contractile response to stress, altered diastolic relaxation, downregulation of β-adrenergic receptors, and electrophysiological changes as a result of cirrhotic cardiomyopathy.

Echocardiographic examination of cardiac function may initially be interpreted as normal because of significant afterload reduction caused by low systemic vascular resistance. However, both systolic and diastolic dysfunction are often present. Noninvasive stress imaging is frequently used to assess coronary artery disease in patients older than age 50 years and in those with cardiac risk factors.

Hepatopulmonary Syndrome

The effects of hepatic cirrhosis on pulmonary vascular resistance (PVR) vessels may result in vasodilation, causing shunts and chronic hypoxemia, or conversely lead to pulmonary vasoconstriction and medial hyperplasia, causing an increase in vascular resistance and pulmonary hypertension. Hepatopulmonary syndrome (HPS; Table 34–7) is found in approximately 30% of liver transplant candidates and is characterized by a triad of decreased oxygen saturation in the presence of advanced liver disease and intrapulmonary arteriolar dilation. Intrapulmonary vascular dilation causes intrapulmonary right-to-left shunting and an increase in the alveolar-to-arterial oxygen gradient.

Pulse oximetry may be used to screen for HPS, and room air SpO₂ less than 96% requires investigation. There is no medical treatment for HPS, which is progressive, but it is reversed over 6 months to 2 years by liver transplantation.

Portopulmonary Hypertension

Pulmonary vascular remodeling may occur in association with chronic liver disease, involving vascular smooth muscle proliferation, vasoconstriction, intimal proliferation, and eventual fibrosis, all presenting as obstruction causing an increased resistance to pulmonary blood flow. These pathological changes may result in pulmonary hypertension, and if associated with portal hypertension, the condition is termed portopulmonary hypertension (POPH; Table 34–8).

The diagnostic criteria for POPH include a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg at rest, and a PVR greater than 240 dyn·s·cm^–5. The transpulmonary gradient of greater than 12 mm Hg (mPAP minus pulmonary arteriolar occlusion pressure [PAOP]) reflects the obstruction to flow and distinguishes the contribution of volume and resistance to the increase in mPAP.

POPH may be classified as mild (mPAP 25–35 mm Hg), moderate (mPAP >35 and <45 mm Hg), and severe (mPAP >45 mm Hg). Mild POPH is not associated with increased mortality at liver transplantation, although the immediate recovery period may be challenging if there is significant increase in cardiac output after reperfusion of the new graft. Moderate and severe POPH are associated with significant mortality at transplantation. However, the key factor is not mPAP, but rather right ventricular (RV) function.

The success of liver transplantation will depend on the right ventricle maintaining good function during and after the transplant procedure despite increases in cardiac output, volume, and PVR. If RV dysfunction or failure occurs, graft congestion with possible graft failure and possible mortality may ensue. Assessment of the right ventricle using transesophageal echocardiography (TEE) is often helpful.

The role of liver transplantation in the management of POPH is not well defined. In some patients, pulmonary hypertension will reverse quickly after transplant; however, other patients may require months or years of ongoing vasodilator therapy. Yet other patients may continue to progress and eventually develop RV failure. Some patients with HPS develop pulmonary hypertension after liver transplantation, suggesting that both pathologies may occur simultaneously. Liver transplantation offers the best outcome in patients with POPH that is responsive to vasodilator therapy.

D. Respiratory Manifestations

Disturbances in pulmonary gas exchange and ventilatory mechanics are often present. Hyperventilation is common and results in a primary respiratory alkalosis. As previously noted, hypoxemia is frequently present and is due to right-to-left shunting of up to 40% of cardiac output. Shunting is due to an increase in both pulmonary arteriovenous communications (absolute) and ventilation/perfusion mismatching (relative). Elevation of the diaphragm from ascites decreases lung volumes, particularly functional residual capacity, and predisposes to atelectasis. Moreover, large amounts of ascites produce a restrictive ventilatory defect that increases the work of breathing. Severe hydrothorax is also frequently found.

Review of the chest radiograph and arterial blood gas measurements is useful preoperatively because atelectasis and hypoxemia are usually not evident on clinical examination. Paracentesis should be considered in patients with massive ascites and pulmonary compromise, but should be performed with caution because excessive fluid removal can lead to circulatory collapse.

E. Renal Manifestations and Fluid Balance

Derangements of fluid and electrolyte balance may manifest as ascites, edema, electrolyte disturbances, and hepatorenal syndrome (see below). Important mechanisms responsible for ascites include (1) portal hypertension, which increases hydrostatic pressure and favors transudation of fluid across the intestine into the peritoneal cavity; (2) hypoalbuminemia, which decreases plasma oncotic pressure and favors fluid transudation; (3) seepage of protein-rich lymphatic fluid from the serosal surface of the liver secondary to distortion and obstruction of lymphatic channels in the liver; and (4) avid renal sodium and water retention.

Patients with cirrhosis and ascites have decreased renal perfusion, altered intrarenal hemodynamics, enhanced proximal and distal sodium reabsorption, and often an impairment of free water clearance. Hyponatremia and hypokalemia are common. The former is dilutional, whereas the latter is due to excessive urinary potassium losses from secondary hyperaldosteronism or from diuretics. The most severe expression of these abnormalities is seen with the development of hepatorenal syndrome. Patients with ascites have elevated levels of circulating catecholamines, probably due to enhanced sympathetic outflow. In addition to increased renin and angiotensin II, these patients are insensitive to circulating atrial natriuretic peptide.

Hepatorenal syndrome is a functional renal defect in patients with cirrhosis that usually follows gastrointestinal bleeding, aggressive diuresis, sepsis, or major surgery. It is characterized by increased renal vasoconstriction, which may be a response to splanchnic vasodilation, reduced glomerular filtration rate, progressive oliguria with avid sodium retention, azotemia, intractable ascites, and very high mortality rate. Treatment is supportive and often unsuccessful unless liver transplantation is undertaken.

Judicious perioperative fluid management in patients with advanced liver disease is critical. The importance of preserving perioperative kidney function cannot be overemphasized. Overzealous preoperative diuresis should be avoided, and acute intravascular fluid deficits should be corrected with colloid infusions. Diuresis of ascites and edema fluid should be accomplished over several days. Loop diuretics are administered only after measures such as bed rest, sodium restriction (<2 g NaCl/d), and spironolactone administration are found to be ineffective. Daily body weight measurements are useful in preventing intravascular volume depletion during diuresis; in patients with both ascites and peripheral edema, no more than 1 kg/d should be lost during diuresis, and in those with ascites alone, no more than 0.5 kg/d should be lost. Hyponatremia (serum [Na⁺] <130 mEq/L) also requires water restriction (<1.5 L/d), and potassium deficits should be replaced preoperatively. Medical treatment includes albumin infusions in combination with vasoconstrictors such as vasopressin, midodrine, and norepinephrine, and perhaps the vasopressin analogue, terlipressin. Prolonged kidney impairment will result in acute tubular necrosis, and if this occurs a liver–kidney transplant may be indicated.

F. Central Nervous System Manifestations

Hepatic encephalopathy is characterized by mental status alterations with fluctuating neurological signs (asterixis, hyperreflexia, or inverted plantar reflex) and characteristic electroencephalographic changes (symmetric high-voltage, slow-wave activity). This is associated with accumulation of neurotoxins, including ammonia and short-chain fatty acids. Some patients also have elevated intracranial pressure. Metabolic encephalopathy seems to be proportionately related to both the amount of hepatocellular damage present and the degree of shunting of portal blood away from the liver and directly into the systemic circulation. The accumulation of substances originating in the gastrointestinal tract (but normally metabolized by the liver) has been implicated. Factors known to precipitate hepatic encephalopathy include gastrointestinal bleeding, increased dietary protein intake, hypokalemic alkalosis from vomiting or diuresis, infections, worsening liver function, and drugs with central nervous system depressant activity.

Hepatic encephalopathy should be aggressively treated preoperatively. Precipitating causes should be corrected. Oral lactulose (30–50 mL every 8 h) or neomycin (500 mg every 6 h) is useful in reducing intestinal ammonia absorption. Lactulose acts as an osmotic laxative, and, like neomycin, likely inhibits ammonia production by intestinal bacteria. Sedatives, especially benzodiazepines, should be avoided as they may precipitate hepatic coma.

Intraoperative Considerations

Patients with postnecrotic cirrhosis due to hepatitis B or hepatitis C who are carriers of the virus may be infectious. Universal precautions are always indicated in preventing contact with blood and body fluids from all patients.

A. Drug Responses

The response to anesthetic agents is unpredictable in patients with cirrhosis. Changes in central nervous system sensitivity, volumes of distribution, protein binding, drug metabolism, and drug elimination are common. An increase in the volume of distribution for highly ionized drugs, such as neuromuscular blockers (NMBs), is due to the expanded extracellular fluid compartment; an apparent resistance may be observed, requiring larger than normal loading doses. However, smaller than normal maintenance doses of NMBs dependent on hepatic elimination (pancuronium, rocuronium, and vecuronium) are needed. The duration of action of succinylcholine may be prolonged because of reduced levels of pseudocholinesterase, but this is rarely of clinical consequence.

B. Anesthetic Technique

The cirrhotic liver is very dependent on hepatic arterial perfusion because of reduced portal venous blood flow. Preservation of hepatic arterial blood flow and avoidance of agents with potentially adverse effects on hepatic function are critical. Regional anesthesia may be used in patients without thrombocytopenia or coagulopathy, but hypotension must be avoided. A propofol induction followed by isoflurane or sevoflurane with an oxygen–air mixture is commonly employed for general anesthesia. Opioid supplementation reduces the dose of the volatile agent required, but the half-lives of opioids are often significantly prolonged, which may cause postoperative respiratory depression. Cisatracurium may be the NMB of choice because of its nonhepatic metabolism.

Preoperative nausea, vomiting, upper gastrointestinal bleeding, and abdominal distention due to massive ascites require a well-planned anesthetic induction. Preoxygenation and rapid-sequence induction/intubation with cricoid pressure are often performed. For unstable patients and those with active bleeding, either an awake intubation or a rapid-sequence induction using ketamine or etomidate and succinylcholine is suggested.

C. Monitoring

Pulse oximetry should be supplemented with arterial blood gas measurements to monitor acid–base status. Patients with large right-to-left intrapulmonary shunts may not tolerate the addition of nitrous oxide and may require positive end-expiratory pressure (PEEP) to treat ventilation/perfusion inequalities and associated hypoxemia. Patients receiving vasopressin infusions should be monitored for myocardial ischemia due to coronary vasoconstriction.

Continuous intraarterial pressure monitoring is often used because hemodynamic instability frequently occurs as a result of excessive bleeding and operative manipulations. Intravascular volume status is often difficult to optimize, and goal-directed hemodynamic and fluid therapy utilizing esophageal Doppler, arterial waveform analysis, pleth variability index (PVI), or TEE should be considered. Such approaches may be helpful in preventing acute kidney injury. Urinary output must be followed closely; mannitol may be considered for persistently low urinary outputs despite adequate intravascular fluid replacement.

D. Fluid Replacement

Most patients are sodium-restricted preoperatively, but preservation of intravascular volume and urinary output takes priority intraoperatively. The use of predominantly colloid intravenous fluids (albumin) may be preferable to avoid sodium overload and to increase plasma oncotic pressure. Intravenous fluid replacement should take into account the excessive bleeding and fluid shifts that often occur in these patients during abdominal procedures. Venous engorgement from portal hypertension, varices, lysis of adhesions from previous surgery, and coagulopathy lead to excessive bleeding during surgical procedures, whereas evacuation of ascites and prolonged surgical procedures result in large fluid shifts. Following the removal of large amounts of ascitic fluid, aggressive intravenous fluid replacement is often necessary to prevent profound hypotension and acute kidney injury or failure. Liberal use of crystalloid solutions may result in widespread edema because of the low serum albumin, and colloid solutions are usually more appropriate.

Most preoperative patients are anemic and coagulopathic, and perioperative red blood cell transfusion may lead to hypocalcemia from impaired citrate metabolism in the cirrhotic liver. Citrate, the anticoagulant in stored red blood cell preparations, binds with plasma calcium, producing hypocalcemia. Intravenous calcium may be necessary (see Chapter 51).

Common hepatic procedures include repair of lacerations, drainage of abscesses, and resection of primary or metastatic neoplasms, and up to 80% to 85% of the liver can be resected in many patients. In addition, liver transplantation is performed in many centers. The perioperative care of patients undergoing hepatic surgery is often challenging because of coexisting medical problems and debilitation found in many patients with intrinsic liver disease, and because of the potential for significant operative blood loss. Hepatitis and cirrhosis greatly complicate anesthetic management and increase perioperative mortality. Multiple large-bore intravenous catheters and fluid blood warmers are necessary; rapid infusion devices facilitate management when massive blood transfusion is anticipated. Continuous intraarterial pressure monitoring is typically utilized.

Hemodynamic optimization is often complicated by the conflict between the need to maintain sufficient intravascular volume to ensure adequate hepatic perfusion and the need to keep central venous pressure low to minimize liver engorgement and surgical bleeding. Central venous pressure measurement is not an accurate monitor of volume status; we suggest goal-directed fluid therapy utilizing esophageal Doppler, arterial waveform analysis, PVI, or TEE. Care should be taken in placing an esophageal Doppler or TEE probe in a patient with esophageal variceal disease.

Hypotensive anesthesia should be avoided because of its potentially deleterious effects on liver function. Administration of antifibrinolytics, such as ε-aminocaproic acid or tranexamic acid, may reduce operative blood loss, especially if fibrinolysis can be demonstrated by viscoelastic coagulation monitoring. Hypoglycemia, coagulopathy, and sepsis may occur following large liver resections. Drainage of an abscess or cyst may be complicated by peritoneal contamination. In the case of a hydatid cyst, spillage can cause anaphylaxis due to the release of Echinococcus antigens.

Postoperative complications include hepatic dysfunction, sepsis, and blood loss secondary to coagulopathy or surgical bleeding. Postoperative pain from the surgical incision may hinder postoperative mobilization and convalescence, but perioperative coagulopathy may limit the use of epidural analgesia. Transversus abdominis plane (TAP) blocks may be very effective. Postoperative mechanical ventilation may be necessary in patients who have undergone extensive resections or who are markedly debilitated.

Liver Transplantation

When a center opens a liver transplantation program, a credentialed director should be appointed who should be an anesthesiologist with experience and training in liver transplantation anesthesia. A dedicated team of anesthesiologists should be assembled to manage the perioperative course of all liver transplantation patients. This team should have a thorough understanding of the indications for, and contraindications to, liver transplantation (Tables 34–9 and 34–10), as well as the perioperative implications of associated comorbidities such as coronary artery disease, cirrhotic cardiomyopathy, portopulmonary hypertension, HPS, hepatorenal syndrome, and hepatic encephalopathy and cerebral edema. It has been demonstrated that such an approach improves outcomes, as measured by reduced blood transfusions, the need for postoperative mechanical ventilation, and the intensive care unit length of stay.

Preoperative Considerations

The Model for End-stage Liver Disease (MELD) score is used by the United Network for Organ Sharing (UNOS) to prioritize patients on the liver transplantation waiting list. The score is based on the patient’s serum bilirubin, serum creatinine, and INR, and is a predictor of survival time if the patient does not receive a liver transplant. A score of 20 predicts a 20% risk of mortality at 3 months, whereas a score of 40 predicts a 71% risk of mortality at 3 months (Figure 34–1).

Multiply the resulting value by 10, and round to nearest whole number. The minimum for all values is 1.0; the maximum value for creatinine is 4.0.

Most liver transplant candidates have high MELD scores and present with jaundice, kidney failure, and coagulopathy. They may also be emaciated and have massive ascites, and some may have encephalopathy, HPS, cirrhotic cardiomyopathy, and POPH. These patients often have an increased cardiac index and reduced systemic vascular resistance.

Significant blood loss may be anticipated, and large-bore intravenous catheters should be placed for access. A rapid infusion pump should be available. Routine hemodynamic monitoring should include intraarterial pressure monitoring. TEE is routinely utilized in many centers. Pulmonary artery catheterization, once routine, has now been replaced by a central venous catheter at many centers, except when there is concern for POPH or cirrhotic cardiomyopathy.

The immediate availability of intraoperative continuous venovenous hemodialysis (CVVHD) may be very helpful for volume and electrolyte management in the patient with marginal or no kidney function. In patients with significant electrolyte abnormalities, serum sodium and potassium can be closely managed by adjusting the CVVHD dialysate solution.

Intraoperative Management

As previously noted, hepatic disease causes endothelial dysfunction that impairs all organs of the body. The heart develops cirrhotic cardiomyopathy; the brain, encephalopathy and eventual cerebral edema; the kidneys, hepatorenal syndrome and eventual acute tubular necrosis; and the lungs, HPS or portopulmonary hypertension, or both. Therefore, each organ must be carefully managed throughout the operative procedure and postoperative period.

Maintenance of cerebral perfusion pressure (CPP) is particularly important in patients with cerebral edema, and some centers will monitor intracranial pressure. Additional cerebral protective measures include head elevation of 20°, mild hypothermia, and mild hypocarbia with vasopressor support to maintain mean arterial pressure. When the patient’s head is elevated, the arterial pressure transducer should be zeroed at the level of the external auditory meatus for accurate determination of CPP.

Coagulopathy is managed with the aid of a point-of-care viscoelastic coagulation assay device (TEG, ROTEM, or Sonoclot) or frequent assessment of conventional tests of coagulation. Blood loss may be large, and transfusions are targeted to maintain the hemoglobin level at greater than 7 g/dL.

Transfusions must be tempered to keep the central venous pressure (CVP) low during the liver dissection to reduce blood loss and minimize liver congestion, and during reperfusion and the remainder of the procedure to prevent graft congestion and hepatic dysfunction. Most coagulopathies will correct with the new liver if its function is good. Fibrinolysis, a low ionized calcium level, and hypothermia must be corrected, as these may promote bleeding. However, coagulation defects usually do not need to be treated preoperatively or intraoperatively unless bleeding is a problem. Intraoperative transfusion of platelets and fresh frozen plasma is associated with decreased long-term patient survival.

The liver transplantation surgical procedure is divided into three stages: the dissection (preanhepatic), anhepatic, and neohepatic periods.

The dissection (preanhepatic) phase is highlighted by the management of hemodynamic changes related to blood loss and surgical compression of major vessels. Surgical entry into a large varix may lead to large blood loss. Hyponatremia should be carefully managed without rapid serum sodium correction, because this may promote the development of osmotic demyelination syndrome. Hyperkalemia may require aggressive intervention with diuresis, transfusion of only washed packed red blood cells, or CVVHD. Citrate toxicity (hypocalcemia) may occur if blood is transfused; therefore, ionized calcium should be closely monitored, and calcium salts administered as necessary. A low CVP is helpful to minimize blood loss while systemic arterial pressure is maintained.

The anhepatic phase begins with the vascular occlusion of the inflow to the liver and ends with reperfusion. Some centers utilize venovenous bypass to prevent congestion of the visceral organs, improve venous return, and possibly protect kidney function.

In the neohepatic phase, two pathophysiological events may occur on opening the portal vein and allowing reperfusion of the graft. The first is a reperfusion syndrome caused by the cold, acidotic, hyperkalemic solution that may contain emboli and vasoactive substances being flushed from the graft directly into the vena cava. This may cause hypotension, right heart dysfunction, arrhythmias, and even cardiac arrest, and may be preempted to some extent by the prophylactic administration of calcium chloride and sodium bicarbonate. The second syndrome that may occur is ischemia/reperfusion injury. This may result from impaired reperfusion due to severe endothelial dysfunction, and, in rare cases, may lead to primary nonfunction of the graft.

Postoperative Management

Patients who undergo liver transplantation are often severely debilitated and malnourished and have multiorgan dysfunction. They will need careful support and continuous monitoring until they have recovered. Early extubation is appropriate in patients who are comfortable, cooperative, and not excessively coagulopathic. Immunosuppression must be carefully managed to minimize risk of sepsis. A close watch of graft function must be maintained, with a low threshold for checking hepatic artery patency and flow. Postoperative bleeding, biliary leaks, and vascular thromboses may require surgical reexploration.

Patients with elevated intracranial pressure (ICP) and those at risk of its development should have ICP monitoring in place, if possible, to enable the appropriate management of CPP. The management of patients who are at risk of or have elevated ICP should include the following:

• ICP less than 20 mm Hg

• CPP greater than 50 mm Hg

• Mean arterial pressure greater than 60 mm Hg

• Proper bed position (elevate the head of the bed by 20–25°)

• Controlled airway and ventilation

• Controlled sedation (eg, propofol)

• Vasopressor support (eg, vasopressin, norepinephrine) when necessary

• Controlled hypothermia (32–33°C)

• Glycemic control

• Aggressive treatment of metabolic acidosis and coagulopathy

• CVVHD

Pediatric Liver Transplantation

Selected pediatric centers report 1-year survival rates of 90%. The use of reduced-size and living donor grafts has increased the organ availability in this patient population.

Living Donor Transplantation

The use of living donors has increased the pool of organs available for transplantation. However, this procedure does expose healthy individuals to morbidity and mortality risks. Informed consent from the donor must be obtained with the understanding that there is often a great deal of emotional pressure on family members to donate, and that consent must be freely given without coercion.

In most donor anesthesia protocols, maintenance of a CVP less than 5 cm H₂O is utilized to reduce intraoperative blood loss. Adequate postoperative analgesia is required so that comfortable donor patients may be extubated at the end of the procedure. TAP blocks meet this need. Complications of this surgery for the donor patient include transient hepatic dysfunction, wound infection, postoperative bleeding, portal vein thrombosis, biliary leaks, and, rarely, death. An increased incidence of perioperative brachial plexus injury has been reported in donor patients.