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ACS Surgery: Principles and Practice

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10 HEPATIC FAILUR E Walid S. Arnaout, M.D., and Achilles A. Demetriou, M.D., Ph.D.

Approach to the Patient with Liver Failure Hepatic failure and cirrhosis continue to be major causes of morbidity and mortality among critically ill patients. Since the beginning of the 1980s, several advances have been made in the management of hepatic failure. Newer diagnostic techniques and therapeutic modalities have been introduced that have led to significantly better overall outcomes. In addition to improved medical therapy, liver transplantation has proved to be effective in treating end-stage liver disease and liver failure, regardless of etiology. In what follows, we outline general management guidelines for hepatic failure and its complications. We also discuss the role of artificial liver support and its potential use in managing hepatic failure. Patient Evaluation RISK FACTORS AND WORKUP

Liver disease is usually suspected on the basis of several risk factors, including a history of alcohol or I.V. drug abuse. Receipt of a blood transfusion before 1992 raises the index of suspicion for viral hepatitis, hepatitis C virus (HCV) infection in particular.1-3 Other risk factors for liver disease are tattoos, sexual promiscuity, and snorting cocaine. Rare risk factors include a family history of certain liver diseases and exposure to various toxins and chemicals (e.g., aflatoxin and carbon tetrachloride). Evaluation of patients with suspected liver disease is often complex and typically requires an extensive workup—including a detailed history and physical examination as well as various diagnostic studies—to establish the diagnosis and confirm the underlying cause. The laboratory data usually required include a complete blood count, a platelet count, liver function tests, a prothrombin time (PT), and serum albumin and cholesterol levels. In addition, imaging studies (e.g., abdominal ultrasonography, computed tomography, or magnetic resonance imaging) may be indicated. These studies usually demonstrate anatomic and structural abnormalities in the liver parenchyma, the biliary tree, or the vascular system. Occasionally, a liver biopsy is required to establish or confirm the diagnosis of liver disease. Liver disease commonly gives rise to several manifestations that are easily recognized by most health care workers: jaundice [see 3:4 Jaundice], muscle wasting, malnutrition, ascites, lower-extremity edema, and varying degrees of hepatic encephalopathy. Common findings on physical examination of patients with liver disease in-

clude bitemporal muscle wasting, vascular spiders, abdominal wall collaterals, caput medusae, palmar erythema, and clubbing. Umbilical and inguinal hernias are frequently noted in patients with tense ascites. Bilateral gynecomastia and testicular atrophy are often seen in male patients. PRIMARY VERSUS SECONDARY HEPATIC FAILURE

Hepatic failure is generally classified as either primary or secondary, depending on the underlying cause. Primary hepatic failure derives from underlying liver disease, whereas secondary hepatic failure is caused by various underlying conditions unrelated to the liver. Most patients with primary hepatic failure have a history of preexisting liver disease and possibly of cirrhosis, generally presenting with one or more complications of chronic liver disease (e.g., GI bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, or renal failure). A subgroup of patients, however, exhibit hepatic failure secondary to acute exacerbation of the preexisting liver disease (e.g., acute reactivation of hepatitis B, acute decompensated Wilson disease, or autoimmune hepatitis). In another subgroup, primary hepatic failure develops acutely among patients who have no preexisting liver disease and no known risk factors (so-called acute or fulminant hepatic failure).These patients present with massive liver necrosis, jaundice, and profound coagulopathy and often go on to experience deep coma and cerebral edema, which may lead to irreversible brain damage and death. Acute liver failure can be associated with severe multisystem organ involvement, as in the acute respiratory distress syndrome (ARDS) or the multiple organ dysfunction syndrome (MODS), which makes diagnosis difficult. (This may also be the case with chronic liver disease, but to a lesser degree.) Secondary liver failure is seen among critically ill patients admitted to the ICU for management of a non–liver-related illness. It is usually manifested by cholestatic jaundice, impaired synthetic activity, varying degrees of hepatocellular damage, and altered mental status. Hepatic insufficiency is common in patients with life-threatening injuries, severe systemic infection, or ARDS. These patients usually have no preexisting liver disease: their liver dysfunction is simply a reflection of their overall critical condition. The extent of the liver dysfunction in such cases usually depends on the severity of the underlying nonhepatic disease; in general, it tends to lessen as the causative problem is controlled or resolved. Failure to control the primary underlying condition leads to progressive MODS and death. Management of secondary hepatic failure typically involves treating underlying nonhepatic disorders. Accordingly, we focus here on management of acute and chronic primary hepatic failure, which by definition involves treating hepatic disease and its associated complications.

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ACS Surgery: Principles and Practice

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Approach to the Patient with Liver Failure

Patient has signs of liver disease or known risk factors Perform extensive workup: history, physical examination, laboratory tests, and imaging studies as needed. Liver biopsy is occasionally required. Distinguish primary from secondary hepatic failure.

Primary hepatic failure

Acute liver failure Determine etiology—viral, drug-induced, toxin-induced, or other—and treat accordingly. Begin medical management of complications. Concurrently, assess prognosis by means of King's College criteria.

Cerebral edema

Extrahepatic complications

Initiate invasive ICP monitoring. Manage elevated ICP.

Treat fluid, electrolyte, and nutritional abnormalities; renal failure; pulmonary complications; infectious complications; and coagulopathy and bleeding.

Good prognosis with medical management

Poor prognosis with medical management

Continue medical therapy.

Medical management succeeds

Medical management fails Consider emergency OLT if not contraindicated. Treat toxic liver syndrome with total hepatectomy and end-to-side portacaval shunt, followed by OLT. Consider use of BAL support system.

Transplantation is contraindicated Manage medically.

No contraindications to transplantation are present

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ACS Surgery: Principles and Practice

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Secondary hepatic failure Treat underlying nonhepatic cause.

Chronic liver disease Determine etiology [see Table 4], and treat accordingly. Begin medical management of complications.

Portal hypertension Treat complications of PHT: • Variceal bleeding • Ascites: restrict sodium and give diuretics. If medical management fails, perform LVP or use a shunt (peritoneovenous or TIPS).

Hepatic encephalopathy Control precipitating factors, and control ammonia levels with lactulose or antibiotics.

Malnutrition

Renal failure Treat HRS, ATN, RTA, and drug-induced interstitial nephritis. Correct underlying causes. Manage fluids and electrolytes carefully.

Medical management is unsatisfactory, and no contraindications to transplantation are present

GIve glucose with fat emulsion. Use enteral feeding unless contraindicated.

Medical management is satisfactory, or transplantation is contraindicated Manage medically.

Perform OLT when donor organ is available. Consider use of BAL support system while awaiting organ.

Coagulopathy and bleeding Identify hemostatic defect. Give FFP, cryoprecipitate, prothrombin complex concentrates, platelets, AT-III concentrate, or antifibrinolytic agents as appropriate.

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ACS Surgery: Principles and Practice

6 Critical Care Acute Liver Failure

In the United States, acute liver failure (ALF) affects approximately 5,000 persons each year.The definition of ALF depends on the temporal relation between the initial onset of illness and the manifestation of jaundice, encephalopathy, and coagulopathy.The classic definition of Trey and Davidson is based on massive liver necrosis associated with encephalopathy developing within 8 weeks of the onset of illness.4 In most cases, however, it is difficult to determine the precise time of onset of the disease process and thus the exact time elapsed before the establishment of hepatic failure. Recognizing that clinical findings and prognosis varied depending on the interval between onset of jaundice and encephalopathy, Bernuau and coworkers defined fulminant hepatic failure (FHF) as ALF complicated by encephalopathy developing within 2 weeks of the onset of jaundice and defined subfulminant hepatic failure (SFHF) as ALF complicated by encephalopathy developing 2 to 12 weeks after onset of jaundice.5 Differences in nomenclature and classification notwithstanding, the defining characteristic of ALF is the absence of known preexisting liver disease.We use the term FHF more or less interchangeably with ALF as defined by Trey and Davidson. ETIOLOGY

The causes of FHF may be classified into four major groups: viral, drug-induced, toxin-induced, and miscellaneous. In one multicenter study, acetaminophen-induced FHF toxicity was found to be the most common variety (20%), followed by FHF of indeterminate etiology (15%).6 Viral Hepatitis Hepatitis A The incidence of FHF and SFHF in hepatitis A virus (HAV) infection is very low (< 0.01%).5 Young patients with HAV infection rarely manifest FHF, and their chances of survival with medical therapy are relatively good (40% to 60%). About 10% of patients experience relapses, usually within 2 to 3 months after an initial clinical improvement. Relapse is signaled by an increase in serum transaminase and bilirubin levels and the reappearance of virus in the stool. If encephalopathy occurs during this period, the outcome is poor.7 Hepatitis B ALF related to hepatitis B virus (HBV) accounts for fewer than 1% of HBV infections but is the most common form of viral-induced FHF.6,8 Like HAV infection, HBV infection leads to FHF more often than to SFHF. Hepatitis B surface antigen (HBsAg) and HBV DNA may be absent in some cases of FHF secondary to HBV infection.9 These findings indicate that in certain FHF patients, an enhanced immune response prevents further HBV replication and results in more rapid clearance of HBsAg.The survival rate for patients who are HBsAg-positive on presentation (17%) is much lower than that for patients who are HBsAg-negative (47%).5 Clearance of HBsAg and HBV DNA results in better survival rates as well as lower recurrence rates after emergency liver transplantation.10 Hepatitis D Hepatitis D virus (HDV, also referred to as the delta agent) is a defective virus that uses HBsAg as its envelope protein. HDV RNA is detected in only 10% of patients with fulminant hepatitis D.11 HDV infection can be either a coinfection, in conjunction with HBV infection, or a superinfection in patients with previous HBV infection [see6:20Viral Infection].12 Among patients with FHF,

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HDV coinfection is more common than superinfection; however, HDV superinfection is associated with a higher mortality than HDV coinfection (72% versus 52%) and more often predisposes to chronic liver disease (54% versus 31%).13 Hepatitis C and hepatitis of indeterminate etiology Previously, FHF of indeterminate etiology was attributed to non-A, nonB viral hepatitis. It is now clear that some such cases are caused by hepatitis C virus (HCV) infection, though the precise extent to which HCV infection contributes to this indeterminate group is unclear. Unlike HAV and HBV infection, HCV infection is more likely to cause SFHF than FHF. Despite the availability of advanced serologic testing, there are still many cases of FHF and SFHF whose cause cannot be determined.14,15 These patients are placed into a non-A, non-B, non-C (NANBNC) category, implying a viral etiology. A more accurate designation for this category would be “of indeterminate etiology,” in that the true cause is unknown and may not, in fact, be undiagnosed viral hepatitis. Drugs Drug toxicity accounts for 35% of all cases of FHF and SFHF and usually runs a subfulminant course.6 Drug ingestion causes hepatic injury in fewer than 1% of patients, about 20% of whom manifest FHF or SFHF. Increasing the total drug dose, simultaneously ingesting other drugs that induce or inhibit hepatic enzymes, and continuing drug administration after the onset of liver disease all increase the risk of hepatic failure.5 Acetaminophen toxicity is the most common cause of drug-induced hepatic failure.The prognosis for FHF caused by acetaminophen is usually better than that for FHF caused by other drugs (e.g., isoniazid, psychotropic drugs, antihistamines, and nonsteroidal anti-inflammatory drugs [NSAIDs]).16 Halothane-induced FHF occurs within 2 weeks of general anesthesia and carries a high mortality.17 Toxins Most cases of toxin-induced FHF involve mushroom poisoning or exposure to industrial hydrocarbons. In mushroom poisoning, the active agents are heat-stable and are not destroyed by cooking. Liver damage from mushroom toxins is delayed and is usually preceded by several days of vomiting and diarrhea. Mortality is high: up to 22% in one series.18 Emergency liver transplantation is sometimes successful.19 Industrial hydrocarbons (e.g., carbon tetrachloride and trichloroethylene) are rare causes of FHF. In developing nations, aflatoxin and herbal medicines have been implicated as causes of FHF. Miscellaneous Conditions Wilson disease may present as FHF or SFHF with intravascular hemolysis and renal failure.20,21 A family history of hepatic and neurologic disease, the presence of Kayser-Fleischer rings, and low serum ceruloplasmin levels help establish the diagnosis. Acute decompensated Wilson disease carries a high mortality and is therefore an indication for emergency liver transplantation.22 Acute fatty liver of pregnancy is a rare cause of FHF that carries a high mortality for both mother and infant. Delivery of the fetus results in regression of the microvesicular steatosis and abnormal liver test results for the mother.The risk of FHF is increased with misdiagnosis and continuation of pregnancy. Liver transplantation has been successfully performed.23 Several other conditions and disease processes are known to cause ALF in both adults and children [see Table 1]. ASSESSMENT OF PROGNOSIS

Several prognostic criteria and indicators have been proposed for

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Table 1

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Etiology of Acute Liver Failure

Infectious Viral: hepatitis A, B, C, D, and E and hepatitis of indeterminate etiology; infection by herpes simplex virus, cytomegalovirus, Epstein-Barr virus, or adenovirus Bacterial: Q fever Parasitic: amebiasis

Drugs Toxins Mushrooms: Amanita phalloides, verna, and virosa; Lepiota species Bacillus cereus Hydrocarbons: carbon tetrachloride, trichloroethylene, 2-nitropropane, chloroform Copper Aflatoxin Yellow phosphorus

Miscellaneous conditions Wilson disease Acute fatty liver of pregnancy Reye syndrome Hypoxic liver cell necrosis Hypothermia or hyperthermia Budd-Chiari syndrome Veno-occlusive disease of the liver Autoimmune hepatitis Massive malignant infiltration of the liver Partial hepatectomy Liver transplantation Postjejunoileal bypass Galactosemia Hereditary fructose intolerance Tyrosinemia Erythropoietic protoporphyria Irradiation α 1-Antitrypsin deficiency Niemann-Pick disease Neonatal hemochromatosis Cardiac tamponade Right ventricular failure Circulatory shock Tuberculosis

predicting outcome after optimal medical management of FHF.The two main factors determining the likelihood of survival are (1) the extent of liver necrosis and (2) the potential for hepatocyte regeneration. In a 1989 study, investigators at King’s College Hospital in London compiled a set of indicators for predicting a poor outcome after medical therapy and hence the need for emergency liver transplantation.24 Underlying etiology was the single most important predictive variable. Therefore, patients were divided into two groups, one comprising all cases of acetaminophen-induced FHF and the other all cases of FHF from other causes.Age, degree of encephalopathy, serum pH, PT, interval to onset of encephalopathy, and admission serum creatinine and bilirubin levels also proved to be significant variables [see Table 2]. Patients who met the criteria in either group had a 95% chance of dying with medical therapy alone and were identified as candidates for emergency liver transplantation. The major strength of the King’s College study is that it based patient assessment on parameters that are easily obtained within a few hours of admission to the emergency department. This approach to assessment facilitates early referral of patients with a poor prognosis to a specialized liver unit for evaluation for transplanta-

tion. In another study, plasma factor V level and age were found to be independent predictors of survival.25 The criteria for liver transplantation were the presence of hepatic encephalopathy (stage III or IV) and a factor V level either less than 20% of normal in patients younger than 30 years or less than 30% of normal in patients older than 30 years. In addition to biochemical and synthetic activities, assessment of the residual functional reserve of the liver has been studied as an indicator of prognosis.The ratio of acetoacetate to β-hydroxybutyrate in an arterial blood sample (also known as the arterial ketone body ratio [AKBR]) is thought to reflect hepatic energy status.26 Galactose clearance reflects both residual liver mass and hepatic blood flow.27 This test has long been considered a standard test of liver functional reserve, and newer tests are routinely compared to it. At present, functional assessment tools are not routinely used in patient assessment. The wide variety of potential prognostic indicators for FHF notwithstanding, the King’s College criteria are still the most widely used. These criteria have been validated in several large series and are currently considered the gold standard for predicting outcome in FHF patients undergoing medical management. At our center, we apply the King’s College criteria at admission to predict the likely outcome with medical therapy. Once the initial assessment is completed, the decision for or against emergency evaluation for liver transplantation is made. Evaluation, if indicated, is usually completed within 12 to 24 hours. The evaluation is similar to that of patients with chronic liver disease [see Chronic Liver Disease, below], with a few exceptions. In particular, patients with FHF usually do not have preexisting liver disease; thus, it is vital that the evaluation [see Table 3] reveal the probable cause of liver failure. Unlike chronic liver disease, FHF is associated with cerebral edema and elevated intracranial pressure (ICP), which is the leading cause of death among these patients.Therefore, an extensive neurologic evaluation should be completed before a patient is listed for transplantation. Serial neurologic assessment is necessary to rule out irreversible brain damage and brain-stem herniation; however, previous sedation often makes this step very difficult.

Table 2 King’s College Hospital Prognostic Criteria Predicting Poor Outcome for Patients with FHF

Acetaminophen-induced FHF

pH < 7.30 (irrespective of grade of encephalopathy) or All of the following: PT > 100 sec (INR > 6.5) Serum creatinine > 3.4 g/dl Stage III or IV hepatic encephalopathy

Non–acetaminopheninduced FHF

PT > 100 sec (INR > 6.5) (irrespective of grade of encephalopathy) or Any three of the following (irrespective of grade of encephalopathy): Age < 10 or > 40 yr Etiology: non-A, non-B hepatitis, halothane hepatitis, drug toxicity Duration of jaundice to encephalopathy > 7 days PT 50 sec (INR > 3.5) Serum bilirubin > 17.5 g/dl

FHF—fulminant hepatic failure PT—prothrombin time

INR—international normalized ratio

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ACS Surgery: Principles and Practice

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TREATMENT OF COMPLICATIONS

Table 3 Liver Transplant Evaluation and Workup for FHF Patients

Cerebral Edema Cerebral edema is one of the hallmarks of FHF, and its presence significantly influences management and outcome. Autopsy studies indicate that cerebral edema is present in 80% of patients who die of FHF.28,29 It occurs in advanced stages of FHF and can be recognized by clinical, radiologic, or invasive means. Clinical findings include decerebrate posturing, myoclonus, spastic rigidity, seizure activity, systemic hypertension, bradycardia, hyperventilation, and mydriasis with diminished pupillary response.These findings initially are paroxysmal but later become persistent. Papilledema is a late finding and often does not occur at all, even in the advanced stages of the disease.30 Noninvasive diagnostic modalities (e.g., CT scanning, electroencephalographic monitoring, and transcranial Doppler flow measurement) have not proved helpful for early detection and management of cerebral edema.31,32 CT scanning of the brain is not a sensitive test for detecting early cerebral edema: 25% to 30% of patients with high ICP exhibit no radiographic changes.33 It is, however, useful for ruling out intracranial bleeding. Currently, ICP monitoring is the best means of monitoring intracranial hypertension and is recommended for guiding treatment in patients with stage III or IV encephalopathy. ICP can be measured by using epidural, subdural, or intraventricular catheters. Although epidural catheters are slightly less sensitive to ICP changes, they have the lowest complication rate (3.8%) and lowest rate of fatal hemorrhage (1%).34 Despite a slightly higher complication rate, we prefer subdural catheters: in our view, they offer more reliable ICP monitoring. Institution of ICP monitoring necessitates aggressive treatment of any concomitant coagulopathy. Fresh frozen plasma (FFP) infusions are given to bring the PT below 25 seconds, and platelet transfusions are indicated if the patient has severe thrombocytopenia (platelet count < 50,000/mm3). Once ICP monitoring is established, bolus administration of FFP is repeated as needed to keep the prothrombin time low (international normalized ratio [INR] ≤ 5) so as to reduce the risk of intracranial bleeding. The goal of invasive monitoring is to keep ICP below 15 mm Hg while keeping cerebral perfusion pressure (CPP), which is a better predictor of outcome, above 50 mm Hg. CPP is calculated by subtracting ICP from mean arterial pressure (MAP) [see 6:12 Coma,Seizures, Cognitive Impairment, and Brain Death]. ICP monitoring allows early detection of cerebral edema and hence early introduction of aggressive management.To date, no randomized, controlled trials have addressed the effect of either high ICP or low CPP on outcome after liver transplantation; however, it appears that the persistence of either an ICP higher than 25 mm Hg or a CPP lower than 40 mm Hg for more than 2 hours is associated with an increased risk of irreversible brain damage and a poor outcome.35,36 Management of elevated ICP involves hyperventilation, minimization of external stimuli, deep sedation, elevation of the head, maintenance of hemodynamic stability, and infusion of mannitol. Patients are usually sedated with a short-acting agent (e.g., fentanyl) in small boluses before operation, nasotracheal suction, venipuncture, or line placement. Mechanical hyperventilation lowers ICP by lowering arterial carbon dioxide tension (Paco2 ) to 25 to 30 mm Hg, thereby maximizing cerebral vascular constriction and reducing blood flow. This vascular effect diminishes progressively after 6 hours of therapy, though a clinical response is apparent for days. As many as 80% of patients without renal failure respond to mannitol infusions.37 Serum

Laboratory workup CBC and differential count Chemistry panel Coagulation profile 24-hr creatinine clearance Urinalysis Arterial blood gases ANA, AMA, ceruloplasmin, urinary copper, α 1-antitrypsin AFP RPR Thyroid function tests Alcohol and drug toxicology screen

Viral serologies Hepatitis A virus (IgM, IgG) Hepatitis B virus (HBsAg, HBcAb, HBeAg, HBV DNA) Hepatitis C virus (HCV antibody, HCV RNA-PCR) Cytomegalovirus Epstein-Barr virus HIV

Cultures Bacterial, fungal, and viral cultures Blood Sputum Urine Ascites

12-lead ECG Chest x-ray Pulmonary function tests Abdominal Doppler ultrasonography CT scans of head AFP—α-fetoprotein AMA—antimitochondrial antibody body RPR—rapid plasma reagent

ANA—antinuclear anti-

osmolality should be measured frequently and maintained at 300 to 320 mOsm/L. Mannitol should be withheld if osmolality reaches or exceeds 320 mOsm/L, if renal failure occurs, or if oliguria and rising serum osmolality develop simultaneously. Repeated administration of mannitol may reverse the osmotic gradient. Mannitol should be discontinued if ICP does not respond after the first few boluses. Patients who do not respond to conventional therapy may be placed in a barbiturate coma.Thiopental infusion decreases cerebral metabolic activity, lowers CNS oxygen demand, and protects the brain from ischemic injury secondary to decreased cerebral blood flow. In one retrospective, nonrandomized study, it lowered ICP and reduced mortality from FHF.38 In our experience, however, the effect of thiopental infusion on ICP is transient and unpredictable. Other Complications In addition to cerebral edema and increased ICP, MODS and a variety of life-threatening complications are associated with FHF. Most of these complications are similar to those seen in chronic liver disease [see Chronic Liver Disease, Treatment of Complications, below]; however, the following complications are seen with particular frequency in FHF.

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Fluid, electrolyte, and nutritional abnormalities Euvolemia must be maintained to prevent fluid overload, pulmonary edema, and dehydration; extreme fluid shifts should be avoided.The presence of cerebral edema and intracranial hypertension calls for careful fluid administration so as not to expand the intravascular space or exacerbate the edema. Electrolyte and acid-base imbalances are frequent in FHF patients and should be managed appropriately. Hyperkalemia may be multifactorial; usually, it is secondary to liver necrosis, massive transfusion, acid-base imbalance, or renal failure. Acidosis results from increased lactic acid production and decreased handling of lactate by the failing liver. Compensatory respiratory alkalosis develops initially, but if encephalopathy progresses, respiratory acidosis may result. Sodium or potassium bicarbonate infusions should be administered in cases of severe acidosis. Acetate provides twice the bicarbonate load and is metabolized outside the liver; thus, if sodium and potassium intake is severely restricted, continuous infusion of acetate salts may be useful. Initially, amino acids should be withheld to prevent excessive nitrogen loading; later, limited nitrogen supplementation (70 to 80 g protein/day) may be provided. Most patients present with severe hypoglycemia, which can be fatal and warrants aggressive therapy. Hypoglycemia should be corrected rapidly by infusion of a 50% dextrose solution, followed by continuous infusion of a more dilute solution at a rate of 4 mg/kg/min. A 10% solution is usually adequate; however, higher concentrations should be considered in patients whose hypoglycemia persists or whose fluid intake is restricted. Caloric supplementation has not been extensively studied in FHF.

25% of patients, with staphylococci, streptococci, and gram-negative rods the most common pathogens.43 Because most FHF patients have percutaneous lines and indwelling catheters in place, iatrogenic sources must always be considered. Fungal infection is less common than bacterial infection in this setting; however, one series found a significant incidence of fungal infections, with Candida albicans cultured in 33% of the patients studied.44 The majority of these patients had renal failure and had been treated with antibiotics for longer than 5 days. The high prevalence of infection notwithstanding, we do not advocate antibiotic prophylaxis in this population unless there is a strong suspicion of active infection or an ICP monitor is in place. However, our decision threshold for starting antibiotics is low, given that the usual clinical presentations (e.g., fever and leukocytosis) may be absent in as many as 30% of FHF patients.43 Surveillance cultures for bacteria and fungi must be obtained at frequent intervals from blood (peripheral and central lines), urine, sputum, and open wounds. If ascites is present, the ascitic fluid should be cultured. In addition, chest x-rays should be obtained to identify developing infiltrates.Administration of broad-spectrum antibiotics should be initiated at the first sign of infection; as soon as an organism is identified, coverage may be focused more narrowly. Initiation of antifungal therapy with either amphotericin B or another agent should be considered either if fungal culture is positive or if fever persists beyond 5 days while the patient is receiving antibiotics—especially if renal failure is present.The duration of antimicrobial therapy should be individualized for each patient. Follow-up cultures are recommended if a specific organism is isolated.

Renal failure Renal failure occurs in as many as 55% of FHF patients. Functional renal failure is the most common cause of renal failure in this population. However, acute tubular necrosis is more common in these patients than in those with chronic liver disease and cirrhosis.39 This is especially true in patients who have not been resuscitated adequately, who have experienced prolonged hypotension, or who have ingested hepatotoxins that are also nephrotoxic (e.g., acetaminophen). Adequate urine volume can be maintained by means of judicious volume expansion, administration of loop diuretics, or both, along with infusion of renal doses of dopamine. Depleted intravascular volume may be managed by giving blood products, volume expanders, or both. Because the plasma albumin level is invariably low, salt-poor albumin solutions may be preferable to carbohydrate-based volume expanders. If oliguria is present—especially if mannitol is administered to treat ICP—hemodialysis or hemofiltration may be needed to maintain optimal fluid volume.

Coagulopathy and bleeding Bleeding is a frequent complication of FHF, typically resulting from massive liver necrosis, impaired hepatic synthesis of clotting factors, and platelet dysfunction. All clotting factors synthesized by the liver (i.e., factors II,V,VII, IX, and X) exhibit depressed plasma activity in FHF. Factor II, with a halflife of 2 hours, is the first to be depleted with hepatocellular dysfunction and also the first to be repleted with hepatocellular recovery.The PT is invariably prolonged, reflecting a generalized clotting factor deficiency; it is used as one of the criteria for determining the chances of spontaneous recovery. At some centers, FFP transfusion is withheld and the PT is followed carefully to determine upward or downward trends in the course of the disease and hence the likelihood of spontaneous recovery or need for transplantation (unless the PT > 25 seconds or the INR > 5, especially if an ICP monitor is in place). Intracranial bleeding and its neurologic sequelae are the most devastating complications of coagulopathy in FHF patients. Thrombocytopenia and abnormalities of platelet function are also common in FHF. Acute splenomegaly, consumptive coagulopathy, and bone marrow suppression all contribute to the development of thrombocytopenia. Conversely, clearance of older platelets from the blood by the reticuloendothelial system is hindered, which results in an older, less effective platelet pool. In one study, a mean platelet count of 50,000/mm3 was associated with a higher incidence of GI hemorrhage.45 Our current practice is to give platelets to patients who either are thrombocytopenic (platelet count < 50,000/mm3) or are actively bleeding.

Pulmonary complications Pulmonary complications—especially pulmonary edema, aspiration pneumonia, and ARDS—are common in FHF patients.40 Pulmonary edema is seen in as many as 40% of cases. Supplemental oxygen and mechanical ventilation are always indicated. Sedative and paralytic agents may be required to ensure tolerance of ventilation; however, they should be used sparingly because they may hinder neurologic evaluation. Aspiration pneumonia should be treated aggressively because it is a potential contraindication to transplantation. Infectious complications Infection poses a serious threat to FHF patients both by placing them at risk for sepsis and by constituting a contraindication to liver transplantation. Immunologic defects observed in this setting include impaired opsonization, impaired chemotaxis, impaired neutrophil and Kupffer cell function, and complement deficiency.41,42 Bacterial infection, usually deriving from the respiratory or urinary tract or from a central venous catheter, occurs in more than 80% of cases. In one study, bacteremia was documented in

OUTCOME OF MEDICAL THERAPY

Because of the complexity of the underlying disease, medical management of FHF requires a multidisciplinary approach. Hemodynamic and respiratory support and prevention and

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ACS Surgery: Principles and Practice

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treatment of cerebral edema are major goals. Complications of liver failure must be treated aggressively to prevent sepsis, ARDS, and MODS, which is the second most common cause of death in these patients if they survive the first few days. As noted [see Assessment of Prognosis, above], liver transplant evaluation must be carried out simultaneously with aggressive ICU care, and the patient’s chances of spontaneous recovery must be assessed. In addition to determining the King’s College prognostic score at admission, we follow the general trend in the clinical course with respect to the development of encephalopathy, ICP elevation, coagulopathy, metabolic acidosis, and renal failure.The decision whether to continue with medical therapy or to perform liver transplantation must be made whenever a donor liver becomes available. In general, patients who appear to be deteriorating rapidly and who have no contraindications to liver transplantation should undergo emergency liver transplantation. Similarly, patients whose synthetic function does not improve within the first 48 to 72 hours should be considered for liver transplantation: the risk of complications and death from MODS if transplantation is not done outweighs the risk attendant on the procedure. Toxic Liver Syndrome Even with a multidisciplinary, comprehensive approach to therapy, a few patients with FHF go on to manifest the so-called toxic liver syndrome, characterized by severe intracranial hypertension, profound lactic acidosis, hemodynamic instability, and MODS. It has been suggested that removal of the necrotic liver might improve the hemodynamic status of these patients and lower their ICP. In such extreme cases, a two-stage procedure has been performed: total hepatectomy with an end-to-side portacaval shunt, followed by liver transplantation when an allograft becomes available. In one large series,46,47 32 adult patients with toxic liver syndrome underwent total hepatectomy with a portacaval shunt.The patients were anhepatic for several hours (range, 6.5 to 41.4). Whereas 13 patients showed no signs of improvement after hepatectomy and soon died of MODS, 19 became more stable and underwent the full procedure. Only seven patients were alive at 46 months. In the early 1990s, we used this approach to treat an 18-year-old female patient with uncontrollable cerebral edema secondary to FHF; she underwent total hepatectomy with a portacaval shunt, followed by orthotopic liver transplantation (OLT) 14 hours later.48 During the anhepatic period, she was supported with the help of a bioartificial liver (BAL) [see Discussion, Bioartifical Liver Support System, below].With artificial liver support, the severe neurologic dysfunction was reversed, ICP was normalized, and the serum ammonia level was reduced.The patient recovered completely, with no neurologic deficits.We subsequently used the same approach with another FHF patient in our unit, also successfully (unpublished data). It appears that for highly selected patients exhibiting severe toxic metabolic derangement and uncontrollable intracranial hypertension, total hepatectomy with a portacaval shunt—preferably accompanied by some form of artificial liver support—followed by OLT may be considered as a desperate salvage measure. LIVER TRANSPLANTATION

With the introduction of OLT as a treatment modality for FHF patients, overall patient survival has improved from less than 20% to greater than 60%.49,50 As more experience was gained with OLT, it became apparent that optimal patient selection is essential for successful outcome. FHF patients must be considered for OLT before irreversible brain injury, MODS, and sepsis develop. Patient selection should be based on a clear understanding of the natural history

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of the disease as well as of the underlying etiology and the likelihood of spontaneous recovery without transplantation. One of the most difficult aspects of the management of these patients is the lack of reliable prognostic indicators or criteria predicting outcome. In our experience, the King’s College criteria are less sensitive and specific in determining prognosis for patients with acetaminophen-induced FHF than for patients with FHF from other causes (71% and 78% versus 96% and 100%).51 As a result of these imperfectly reliable criteria, a small number of patients who either might have recovered spontaneously or might have sustained irreversible brain damage undergo unnecessary or unwarranted liver transplantation. Given the severe shortage of organ donors as well as the cost and medical consequences of liver transplantation and a commitment to lifelong immunosuppression, this is a significant problem. Chronic Liver Disease

Chronic liver disease usually develops as a result of long-standing, ongoing injury to one or more components of the liver, including the liver parenchyma, the biliary tree, and the hepatic and biliary blood vessels. The repeated injury and the ensuing repair usually result in deposition of excessive amount of extracellular matrix (ECM), with or without accompanying inflammation. As the disease process progresses, excess ECM forms connective tissue bridges linking portal and central areas (so-called bridging fibrosis), which eventually lead to the formation of dense collagen bands enclosing nodules of hepatocytes—that is, to cirrhosis. Cirrhosis is an irreversible state that gives rise to significant physiologic impairment, including poor exchange of nutrients and metabolites between sinusoidal blood and hepatocytes. Eventually, the lobular architecture becomes distorted and blood flow altered, leading to portal hypertension and its numerous complications. In addition to portal hypertension, repeated parenchymal injury results in the loss of a large number of functioning hepatocytes and subsequently in hepatic failure. ETIOLOGY

Like ALF, chronic liver disease is usually classified into various categories on the basis of the underlying causative process [see Table 4 ]. TREATMENT OF COMPLICATIONS

Chronic liver disease may be associated with a variety of complications, depending on the nature and extent of hepatocyte injury and regeneration. Most patients with chronic liver disease and possible cirrhosis are well compensated, maintain a relatively normal functional status, and remain essentially undiagnosed; however, a small percentage eventually become symptomatic. Hepatic failure secondary to cirrhosis is not an all-or-none phenomenon: patients may lose one or more specific liver functions while retaining the remainder. In addition to the hepatic effects, cirrhosis and hepatic failure can exert a wide range of extrahepatic effects that involve virtually every organ system, leading to MODS and death in most cases if appropriate therapy is not instituted promptly. Consequently, treatment of cirrhosis and chronic hepatic failure must focus on treating both the underlying primary disease and all of its extrahepatic manifestations and complications.

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Table 4

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Etiology of Chronic Liver Disease

Alcoholic liver disease (exclude acute alcoholic hepatitis) Viral hepatitis Hepatitis B virus Hepatitis C virus

Biliary cirrhosis Primary biliary cirrhosis Primary sclerosing cholangitis Secondary sclerosing cholangitis Biliary atresia

Autoimmune hepatitis Metabolic abnormalities Wilson disease α 1-Antitrypsin deficiency Hemochromatosis Inborn errors of metabolism

Cryptogenic cirrhosis Miscellaneous Vascular anomalies (Budd-Chiari syndrome) Toxin- or drug-induced Inborn errors of metabolism Other

Portal Hypertension In the majority of patients with chronic liver disease and cirrhosis, portal hypertension (PHT) develops as a result of increased resistance to portal venous blood flow within the liver. PHT is defined as portal venous pressure higher than 12 mm Hg or a hepatic wedge venous pressure that exceeds the inferior vena cava pressure by more than 5 mm Hg. It is classified as prehepatic, hepatic, or posthepatic according to the anatomic site of increased portal venous resistance [see Table 5]. Hepatic PHT is further classified according to the functional relationship to the hepatic sinusoids. Sinusoidal obstruction is more frequently seen with postnecrotic cirrhosis (e.g., from HCV and HBV infection), whereas postsinusoidal obstruction is more common with alcoholic cirrhosis. Prehepatic and posthepatic causes of PHT are less often encountered in patients with cirrhosis; however, efforts should always be made to rule out such causes, because these conditions all require different therapeutic approaches. PHT is associated with numerous complications, most of which are life-threatening if not diagnosed and treated promptly [see Table 6]. Generally, these complications result from adaptive physiologic responses to elevated portal venous pressure, which lead to the development of collateral vessels or shunts to decompress the portal venous system.The absence of valves within the portal venous system allows retrograde portal blood flow into the splenic and mesenteric circulation and rerouting of blood into the systemic circulation through newly formed collaterals. Several portosystemic venous collateral networks have been identified within the GI tract, the peritoneal cavity, the chest, the retroperitoneum, and subcutaneous tissue. Patients with cirrhosis frequently have one or more areas of collateral formation. Variceal bleeding The most dramatic and catastrophic complication of PHT is bleeding from esophageal and gastric varices.

Prompt diagnosis and management are vital. Since the early 1990s, management of variceal bleeding has evolved significantly, thanks to the advent of novel endoscopic therapies and nonoperative portosystemic shunt procedures. Although the esophagus and the stomach are the most common sites of bleeding varices, other sites within the GI tract may be involved as well, including the duodenum, the jejunum, the rectum, and ileostomy and colostomy sites [see Table 7]. The diagnosis and management of gastrointestinal bleeding associated with varices are discussed in more detail elsewhere in this text [see 3:6 Upper Gastrointestinal Bleeding]. Ascites Ascites—that is, leakage of lymph fluid into the peritoneal cavity—is one of the principal clinical manifestations of cirrhosis and PHT. Its appearance is indicative of advanced liver disease and is associated with a poor prognosis.52 It is believed that increased hepatic sinusoidal pressure results in increased formation of lymph and causes hepatic lymph to weep from Glisson’s capsule into the peritoneal cavity. As ascitic fluid accumulates, patients exhibit increasing abdominal distention, which causes abdominal pain, decreased appetite, dyspnea, and, occasionally, pleural effusion (so-called hepatic hydrothorax). Umbilical and inguinal hernias are common in patients with tense ascites. Evaluation. Hepatic ascites should be distinguished from other types of ascites (e.g., chylous, malignant, or cardiac). All patients with ascites should undergo diagnostic paracentesis to characterize the fluid and rule out bacterial peritonitis (see below). In addition, therapeutic large-volume paracentesis (LVP) is indicated for patients who are symptomatic as a result of the large volume of ascitic fluid. Ascitic fluid analysis should include a white blood cell count and a differential count, Gram stain and cultures, and measurement of total protein, albumin, glucose, lactic dehydrogenase (LDH), and

Table 5

Etiology of Portal Hypertension

Prehepatic obstruction Splenic vein thrombosis Portal vein thrombosis Partial nodular transformation

Hepatic obstruction Presinusoidal Idiopathic portal hypertension Schistosomiasis Congenital hepatic fibrosis Sarcoidosis Sinusoidal Nodular regenerative hyperplasia Most forms of cirrhosis Viral hepatitis Acute alcoholic hepatitis Postsinusoidal Alcoholic cirrhosis Veno-occlusive disease

Posthepatic obstruction Budd-Chiari syndrome IVC web Right-sided congestive heart failure/tricuspid valve insufficiency Constrictive pericarditis IVC—inferior vena cava

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Table 6

10 HEPATIC FAILURE — 10

Complications of Portal Hypertension

Variceal bleeding Portal hypertensive gastropathy Ascites Spontaneous bacterial peritonitis Spontaneous shunts Encephalopathy Hypersplenism

amylase concentrations. In addition, the serum albumin level should be measured at the same time so that the serum-ascites albumin gradient (SAAG) may be determined; this value has been shown to correlate directly with portal pressure.53,54 Portal hypertensive ascitic fluid is characterized by a low albumin content, with a SAAG greater than 1.1 g/dl; non–portal hypertensive ascites fluid is characterized by a SAAG less than 1.1 g/dl.55 Spontaneous bacterial peritonitis. An elevated WBC count in the ascitic fluid provides immediate information about possible bacterial infection. Cell counts higher than 500/mm3 suggest bacterial peritonitis, especially when the absolute neutrophil count exceeds 250/mm3.56 More than 20% of cirrhotic patients with ascites eventually manifest bacterial peritonitis—an occurrence known as spontaneous bacterial peritonitis (SBP). Patients with a low total protein level in their ascitic fluid (< 1.5 g/dl) appear to be at highest risk as a result of the reduced complement level and opsonic activity in the fluid. SBP should be considered in any cirrhotic patient with fever, abdominal pain, or worsening encephalopathy or renal function. Ascitic fluid analysis [see Table 8] allows SBP to be distinguished from secondary bacterial peritonitis, which develops as a consequence of an intra-abdominal abscess or a perforated viscus. Once the diagnosis is made, empirical antibiotic therapy is employed until the final culture result becomes available. At present, cefotaxime (or a similar third-generation cephalosporin) is considered the treatment of choice. A dosage of 1 to 2 g I.V. every 6 to 8 hours (depending on renal function) is optimal.Therapy is continued for 14 days.The response to therapy should be monitored by repeating the paracentesis within 48 hours. Ciprofloxacin, either 200 mg I.V. every 12 hours for 7 days or 200 mg I.V. every 12 hours for 2 days followed by 500 mg orally every 12 hours for 5 days, has been shown to be effective as well.57 Currently, it is recommended that antibiotic prophylaxis for SBP (norfloxacin, 400 mg/day) be given only to patients with active GI bleeding and low protein levels in their ascitic fluid or to those who have had SBP before and are awaiting liver transplantation.58 There is no good evidence to support antibiotic prophylaxis in patients whose ascitic fluid protein levels are low and who have never had SBP. Like ascites, SBP carries a grave prognosis: estimated 1-year survival is less than 50% without liver transplantation.59,60

Table 7

ACS Surgery: Principles and Practice

Ectopic Sites for Variceal Bleeding

Site Duodenum Jejunum and ileum Colon Rectum Ileostomy or colostomy Miscellaneous

Frequency 17% 18% 15% 9% 27% 14%

Medical management. Sodium retention is the pathophysiologic hallmark of ascites in cirrhotic patients, and the rate of fluid accumulation is directly related to the amount of sodium retained. Many patients excrete sodium at rates lower than 10 mmol/day, in which case even a modest sodium intake results in a positive sodium balance and continued accumulation of ascitic fluid.Therefore, to achieve effective control of ascites, dietary intake of sodium should be restricted to 1 to 2 g/day (43 to 87 mmol/day).With simple bed rest and salt restriction, ascites can be controlled in about 20% of patients.61 In addition to salt retention, patients with cirrhosis exhibit impaired free water excretion, which may cause hyponatremia. This state appears to be partially attributable to excessive secretion of antidiuretic hormone (ADH) caused by a reduced effective plasma volume.Water intake need not be restricted in all patients with ascites, because many will not become seriously hyponatremic.Water intake should be restricted (to 1.0 to 1.5 L/day) only in patients who become hyponatremic (serum sodium level < 130 mmol/L) and in those who continue to gain weight despite severe sodium restriction and diuretic therapy. Hyponatremia is associated with a variety of neurologic symptoms resembling those of hepatic encephalopathy. Severe hyponatremia (serum sodium < 120 mmol/L), on the other hand, is associated with seizure activity and should be corrected judiciously. Given the risk of the development of demyelinating lesions associated with rapid changes in the serum sodium concentration, it is recommended that correction of serum sodium—mainly by free water restriction to a serum sodium level between 120 and 130 mmol/L—be carried out gradually. Diuretic therapy remains the cornerstone of management of cirrhotic ascites; however, it should be monitored carefully to ensure that intravascular volume depletion, development of prerenal azotemia, and electrolyte imbalances do not occur.The peritoneum can absorb no more than 700 to 900 ml of ascitic fluid a day; accordingly, vigorous diuresis in excess of this amount (in the absence of peripheral edema) results in intravascular volume depletion and renal failure. The two groups of diuretic agents most commonly used to treat ascites are distal tubular–acting agents (e.g., spironolactone) and loop diuretics (e.g., furosemide). Spironolactone inhibits sodium reabsorption in the distal tubules by blocking the effect of serum aldosterone, which is usually elevated in patients with cirrhosis. A spironolactone dosage of 150 to 300 mg/day is sufficient for achieving effective natriuresis in many patients; however, larger dosages (up to 500 to 600 mg/day) may be preferable in certain patients with markedly elevated serum aldosterone concentrations. Adverse effects of spironolactone therapy include hyperkalemia and hyperchloremic acidosis. Tender gynecomastia is also an important side effect; if gynecomastia occurs, amiloride (20 to 40 mg/day) is a good alternative to spironolactone. Furosemide therapy is usually started if the desired diuresis is not achieved with spironolactone or if the urinary sodium-potassium ratio is less than 1. A typical starting dosage is 40 to 80 mg/day, which is gradually increased until adequate diuresis is achieved. Because furosemide causes loss of urinary sodium and potassium, its use may lead to hypokalemia and metabolic alkalosis. Surgical management. Despite large doses of diuretics, some patients become refractory to medical therapy and manifest tense ascites. Abdominal paracentesis is a safe and effective alternative to diuretic therapy and is currently used in patients with poor renal function who cannot tolerate aggressive diuresis and intravascular volume depletion. Most patients tolerate removal of large amounts of ascitic fluid (5 to 10 L) without significant adverse hemodynamic effects.62 Albumin replacement (7 to 9 g/L) with LVP has been asso-

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10 HEPATIC FAILURE — 11

Table 8 Differentiation of Spontaneous Bacterial Peritonitis from Secondary Bacterial Peritonitis through Analysis of Ascitic Fluid Fluid Assay

Spontaneous Bacterial Peritonitis

Secondary Bacterial Peritonitis

WBC (cells/mm 3 )

> 500

> 500

Total protein (g/dl)

< 1.0

> 1.0

Glucose (mg/dl)

> 50

< 50

Lactic dehydrogenase (U/L)

< 225

> 225

Gram stain

Monomicrobial

Polymicrobial

ciated with a significantly lower rate of complications (e.g., hyponatremia, encephalopathy, and renal insufficiency) and is recommended when repeated LVP is indicated.63 In performing paracentesis, one should avoid surgical scars and obvious large subcutaneous collaterals. In general, a point 1 to 2 cm below the umbilicus along the midline is an optimal site in patients with no previous surgical incisions. Ultrasonographic guidance is usually necessary for localization when the amount of fluid present is small and when the fluid is loculated because of earlier episodes of peritonitis or previous surgical procedures. The most common complications of LVP are bleeding, peritonitis, perforated viscus, and intra-abdominal abscess. Other complications (e.g., renal failure and cardiovascular instability) are less common and can usually be prevented by means of albumin and colloid replacement and intravascular volume expansion. A few patients with ascites either become refractory to medical therapy or have contraindications to diuretic therapy or LVP. The usual practice has been to treat these patients with a peritoneovenous shunt through which the ascitic fluid can be reinfused into the systemic circulation, so that effective plasma volume is not reduced.The early enthusiasm for these shunts and their potential advantages notwithstanding, it is clear that there are a number of major complications limiting their use—in particular, early shunt occlusion, disseminated intravascular coagulation (DIC), sepsis, and central venous thrombosis.These complications occur with widely varying degrees of frequency; overall, however, it is estimated that about half of all shunted patients die within 1 year of the operation.64,65 If ascites develops as a result of PHT, it is logical to assume that reduction of the portal pressure might relieve the stimulus for ascites and control its formation. Earlier experience with the side-to-side portacaval shunt showed that this approach effectively controlled ascites; however, about one third of the patients died of postoperative complications and liver failure.66 More recently, the transjugular intrahepatic portosystemic shunt (TIPS) has proved effective in correcting portal hypertension and controlling acute variceal bleeding while carrying low morbidity and mortality.67 These results have led to increasing use of TIPS to manage refractory ascites. In most patients, ascites can be completely or partially controlled with TIPS.68,69 Approximately two thirds of patients with refractory ascites exhibit significantly reduced fluid accumulation and improved renal function.There are, however, a number of complications. Some of these complications are technical (e.g., bleeding from the liver capsule caused by inadvertent puncture, hemobilia, contrast-induced renal failure, and stent malposition or migration). The most significant nontechnical complications associated with the use of TIPS are an increased incidence of encephalopathy

(seen in about 25% to 30% of patients),70,71 hemolysis, and worsening jaundice.72 Stenosis or occlusion of the shunt that necessitates shunt revision is so frequent that it is considered the norm rather than a complication: in most series, 1-year patency rates range from 27% to 57%.73 No long-term follow-up data are available; however, in one study, the overall survival rate was lower among patients who underwent TIPS placement than among those who received repeated LVP.74 These data suggest that whereas TIPS is superior to LVP in controlling refractory ascites, it confers no survival advantage, and most patients will die of other complications of cirrhosis. Hepatic Encephalopathy Hepatic encephalopathy is a complex neuropsychiatric syndrome that arises in patients with severe hepatic insufficiency and cirrhosis. It is characterized by progressive alteration of cognitive function and coordination and depression of consciousness, leading to deep coma. Hepatic encephalopathy takes two main forms: (1) acute encephalopathy associated with FHF and (2) portosystemic encephalopathy (PSE) associated with cirrhosis and portosystemic shunts. It is classified into four stages according to the severity and extent of CNS impairment [see Table 9]. For accurate diagnosis of hepatic encephalopathy, all other disorders that affect cerebral function—including fluid and electrolyte abnormalities, hypoglycemia, azotemia, metabolic acidosis or alkalosis, hypoxia, and plasma hyperosmolality—must be recognized and corrected. Sedatives and paralytic agents should be avoided during the initial assessment period if possible; if sedation or paralysis is required, the combination of poor hepatic function with the shunting of blood away from the liver may greatly lengthen drug elimination, thereby complicating patient assessment. Management of PSE begins with treatment and reversal of all potential precipitating factors: sedatives and other drugs with CNS effects should be discontinued, fluid and electrolyte abnormalities should be corrected, GI bleeding should be controlled, and underlying infectious states (especially SBP) should be treated. Early elective tracheal intubation and airway protection may be necessary in patients with stage III or IV encephalopathy because of the high risk of aspiration and subsequent pneumonia. The classic therapeutic objectives in the management of hepatic

Table 9

Grading of Hepatic Encephalopathy

Encephalopathy Stage

Neurologic Changes

Stage I

Mild confusion, euphoria or depression, decreased attention span, slowing of ability to perform mental tasks, irritability, disorder of sleep pattern

Stage II

Drowsiness, lethargy, gross deficit in ability to perform mental tasks, obvious personality changes, inappropriate behavior, intermittent and short-lived disorientation

Stage III

Somnolent but arousable, unable to perform mental tasks, disorientation with respect to time or place, marked confusion, amnesia, occasional fits of rage, speech present but incomprehensible

Stage IV

Coma

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ACS Surgery: Principles and Practice

6 Critical Care

encephalopathy are (1) to minimize ammonia formation and (2) to augment ammonia elimination [see Discussion, Mechanism of Hepatic Encephalopathy, below]. Lactulose and certain antibiotics are commonly employed to achieve these ends. Lactulose is a synthetic disaccharide cathartic that can be delivered orally, through a nasogastric tube, or via a high enema and can be administered early in the course of the disease.The dosage should begin at 25 g/day and then be titrated to a level at which the patient can produce three or four loose bowel movements a day. Lactulose is neither absorbed nor metabolized in the upper GI tract.When it reaches the colon, the ensuing bacterial degradation acidifies the luminal contents and causes an intraluminal osmotic shift.The more acid environment that results inhibits coliform bacterial growth, thereby reducing ammonia production. Additionally, the low intraluminal gut pH causes ammonia to be converted to ammonium ions, which do not enter the bloodstream easily. Finally, the cathartic action of lactulose clears ammonium ions from the bowel.Aggressive lactulose therapy may induce volume depletion and electrolyte imbalances; metabolic acidosis is a rare occurrence. Neomycin, an agent commonly used for bowel preparation, alters gut flora, especially Escherichia coli and other urease-producing organisms, and thereby causes production of ammonia to fall. Only about 1% of a neomycin dose is absorbed systemically; because of possible ototoxicity and nephrotoxicity, special care should be taken if it is administered on a continuous basis.75 Other oral antibiotics used to treat hepatic encephalopathy are polymyxin B, metronidazole, and vancomycin; they affect gut flora in much the same fashion as neomycin. Aromatic amino acids (AAAs) are known neurotransmitter precursors, and it has been suggested that their products interfere with the activity of true neurotransmitters. It has also been shown that the ratio of branched-chain amino acids (BCAAs) to AAAs in plasma decreases steeply with encephalopathy. Because AAAs and BCAAs compete for the same blood-brain barrier carrier transport sites, the relative paucity of BCAAs leads to increased cerebral uptake of AAAs, which in turn promotes synthesis of false neurotransmitters that then compete with the endogenous transmitters dopamine and norepinephrine.76 Parenteral administration of BCAA-enriched formulas to patients with hepatic encephalopathy has been advocated, but it has not proved beneficial in comparison with administration of conventional parenteral amino acid solutions.77 Renal Failure Liver disease and cirrhosis are commonly associated with functional renal failure—that is, impaired renal function in the absence of significant underlying renal pathology. The most common functional renal abnormality in cirrhotic patients is a condition known as hepatorenal syndrome (HRS). HRS is defined as a reversible state of renal failure characterized by azotemia, oliguria (< 500 ml/day), low urinary sodium excretion (< 10 mEq/L), and an increased urine-plasma osmolality ratio (U/P > 1.0) in the absence of urinary sedimentation. HRS occurs in 18% to 55% of cirrhotic patients with ascites and is characterized by intense renal vasoconstriction, a decreased glomerular filtration rate (GFR), preserved tubular function, and normal renal histology.39,78 Although the exact etiology of HRS is not known, the evidence currently available suggests that it is multifactorial, involving systemic vasodilatation and reduced effective plasma volume along with increased activity of the renin-angiotensin-aldosterone system, which causes further reduction of the GFR. On clinical grounds,

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Table 10 Differentiation of Hepatorenal Syndrome from Acute Tubular Necrosis Hepatorenal Syndrome

Criteria

Acute Tubular Necrosis

Underlying liver disease

Advanced liver damage with jaundice and impaired synthetic function

Mild or severe liver disease

Precipitant

GI bleeding, diuretics, paracentesis, sepsis, or none

Shock, nephrotoxins, sepsis

Onset

Days to weeks

Hours to days

Urinalysis

Renal epithelial cells with or without pigmented granular cells

Pigmented granular casts with or without RBCs, WBCs

Urinary sodium concentration

< 10 mEq/L

> 10 mEq/L

Urinary osmolarity

> Serum osmolarity

Isotonic

Urinary volume

Oliguric

Variable

Course

Progressive, unremitting

Deterioration followed by improved renal function

HRS has been classified into two types: (1) type 1 HRS, in which renal failure is rapidly progressive, as defined by a doubling of the initial serum creatinine level to a value higher than 2.5 mg/dl or a 50% reduction in the initial creatinine clearance to a value lower than 20 ml/min in less than 2 weeks; and (2) type 2 HRS, in which renal failure takes a slower, more gradual course. The prognosis for patients with HRS is poor: to date, all therapeutic approaches have proved unsuccessful. Pharmacologic therapy has consisted of correcting effective volume status and attempting to reverse renal vasoconstriction through I.V. administration of vasodilators (e.g., dopamine, misoprostol, and aminophylline) or drugs that inhibit the synthesis or the effects of endogenous vasoconstrictors (e.g., captopril and thromboxane inhibitors).These approaches have not yielded any effective and reproducible improvements in renal hemodynamics and renal function. Several investigators, however, have reported improved renal function after OLT.79 Subsequently, a newer approach to the management of HRS was introduced that aimed at correcting the primary underlying defect (i.e., systemic vasodilatation) instead of the secondary renal vasoconstriction.Two classes of drugs have been investigated, either individually or in various combinations: (1) agents that inhibit the effects of endogenous systemic vasodilators (e.g., prostacyclin, nitric oxide, and glucagon) and (2) agents that cause systemic vasoconstriction (e.g., ornipressin and terlipressin). In one small series of patients with type 1 HRS, a combination of an oral β-adrenergic drug with midodrine and octreotide led to improved renal function and better long-term outcome.80 Besides functional renal failure, various types of nonfunctional, or organic, renal failure (e.g., acute tubular necrosis [ATN], renal tubular acidosis [RTA], and drug-induced interstitial nephritis) may occur in patients with cirrhosis. ATN is especially common among patients with chronic liver disease or FHF and is usually seen in patients who are poorly resuscitated, have experienced prolonged hypotension, have undergone severe septic episodes, or have ingested hepatotoxins that are also nephrotoxic (e.g., acetaminophen).ATN is characterized by an abrupt rise in blood urea nitrogen (BUN) and serum creatinine

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ACS Surgery: Principles and Practice

6 Critical Care

levels accompanied by oliguria or anuria. Unlike HRS, ATN leads to impairment of the concentrating ability of the tubular system and to excessive urinary sodium excretion; accordingly, a urine sodium concentration higher than 10 mEq/L has been proposed as a diagnostic criterion for ATN in cirrhotic patients [see Table 10]. RTA is commonly seen in patients with primary biliary cirrhosis (PBC), autoimmune liver disease, and alcoholic cirrhosis. It is characterized by an inability of the renal tubules to acidify the urine in the presence of a normal GFR. Management of renal failure is usually aimed at correcting the underlying precipitating causes. In patients with ascites, who experience ongoing loss of fluid and protein into the peritoneum, it is important to maintain an adequate intravascular volume. If intravascular volume is depleted, blood components, volume expanders, or both should be given. Given that the plasma albumin level is invariably low in these patients, salt-poor albumin solutions may be preferable to carbohydrate-based volume expanders. Albumin replacement has been effectively used for volume expansion after LVP.63 Because of the complex interaction between the liver and the kidneys, fluid and electrolyte management often proves exceptionally challenging. In particular, it is difficult to estimate the actual intravascular volume, which is depleted in most cirrhotic patients even though total body fluid volume is higher than normal. Sodium retention and free water retention are the two most common abnormalities of renal function that lead to ascites and dilutional hyponatremia.Typically, sodium retention is an early manifestation, whereas water retention and renal failure are late findings. Nephrotoxic drugs and I.V. contrast agents should be avoided, and dosages of antibiotics and other medications should be adjusted appropriately. Hypernatremia and metabolic acidosis can develop secondary to excessive lactulose therapy and dehydration and cause renal function to deteriorate. Hypokalemia is also common; it develops secondary to increased serum aldosterone concentration, which leads to excessive excretion of potassium in exchange for sodium. Once renal failure develops, hyperkalemia, hypercalcemia, and hyperphosphatemia become significant problems, often necessitating dialysis. Malnutrition Most cirrhotic patients present with depleted glycogen stores, severe proteincalorie malnutrition, and wasting. Impaired hepatic synthetic activity, causing a deficiency of both visceral and structural proteins, is one of the hallmarks of advanced liver disease. In addition, poor appetite, tense ascites, abdominal pain, and excessive loss of protein through repeated LVP and overall increased energy expenditure tend to exacerbate malnutrition. Excessive protein administration can induce hepatic encephalopathy; accordingly, protein intake should be limited to 1 to 1.2 g/kg/day. Glucose is the main energy source given to malnourished cirrhotic patients; however, its use is not without complications, in that these patients typically exhibit glucose intolerance. Lipid emulsion can be safely administered to most patients with liver failure and should be withheld only from patients with overt coma.81 It is generally agreed that the ideal energy source should consist of a mixture of glucose and fat emulsion.Approximately 30% to 40% of all nonprotein calories can be provided in the form of fat.The total energy requirement should be in the range of 25 to 35 kcal/kg/day. As noted [see Hepatic Encephalopathy, above], although AAAs have been implicated in the pathogenesis of hepatic encephalopathy,

10 HEPATIC FAILURE — 13

administration of BCAA solutions has not proved helpful, and the evidence does not support their routine use.77,82 In general, the potential risks and complications associated with total parenteral nutrition (TPN) outweigh the benefits in patients with a functioning GI tract.When properly administered, enteral nutrition is safer, more physiologically correct, and significantly more cost-effective than TPN. It should therefore be considered the first choice for nutritional support in most patients with chronic liver disease unless a contraindication to enteral feeding is present. Coagulopathy and Nonvariceal Bleeding The spectrum of coagulation disorders in patients with liver disease varies from minor localized bleeding to massive life-threatening hemorrhage. Abnormal bleeding may be spontaneous in some patients, but it is more often the result of a hemostatic challenge (e.g., surgical wounds or procedures, gastritis, portal hypertensive gastropathy, gastric or duodenal ulcers, or ruptured varices).The underlying anatomic lesion is believed to be as responsible for bleeding as the hemostatic defect is; accordingly, therapy should be directed at correcting both. Although most bleeding episodes are secondary to decreased synthesis of clotting factors, other causes of bleeding (e.g., defective or dysfunctional factor synthesis and increased consumption of clotting components) must always be ruled out [see 1:4 Bleeding and Transfusion]. In most patients, the decreased levels of clotting factors parallel the progressive loss of parenchymal cell function. Usually, the levels of the vitamin K–dependent factors (i.e., prothrombin, factor VII, factor IX, factor X, protein S, and protein C) fall first, followed by the levels of other factors as cirrhosis progresses. Factor V is synthesized independently of vitamin K availability, and its concentration is of special interest because the plasma factor V level seems to be a predictor of the extent of liver cell damage. Impaired synthesis of coagulation proteins also has an impact on antithrombin III (AT-III), protein C inhibitor, plasminogen, and α 2-antiplasmin as well as on several other inhibitors and activators of both the extrinsic coagulation pathway and the intrinsic pathway.The combination of decreased factor levels and impaired synthesis of coagulation proteins explains the prolongation of the PT, the activated partial thromboplastin time (aPTT), and the thrombin clotting time (TCT) in these patients.83,84 Given the complexity of hemostasis in cirrhotic patients, accurate diagnosis of a bleeding disorder is often hard to achieve. Several disorders and abnormalities may be present simultaneously, and one or more parameters of hemostasis and coagulation may be impaired. Therefore, any effective treatment approach should be broad-based and aimed at correcting several deficiencies or abnormalities at once. FFP contains all of the components of the clotting and fibrinolytic systems but lacks platelets. In most cases, transfusion of 6 to 8 units of FFP suffices to correct severe clotting factor defects; however, the excess volume may not be well tolerated. Cryoprecipitate, the precipitate formed when FFP is thawed at 4°C, is rich in factor VIII, von Willebrand factor, and fibrinogen but lacks the vitamin K–dependent factors.Therefore, it should be given only when the fibrinogen level is lower than 100 mg/dl. Prothrombin complex concentrates contain only the vitamin K–dependent factors and proteins, and their use can provoke serious thromboembolic complications, including disseminated intravascular coagulation (DIC).Therefore, their potential utility must be weighed carefully against the risk that thrombotic events may develop.85

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ACS Surgery: Principles and Practice

VII CARE IN THE ICU

Other major disorders of hemostasis in patients with chronic liver disease and cirrhosis involve platelets and are manifested as thrombocytopenia, abnormal platelet function (thrombocytopathy), or both. In most cases, thrombocytopenia is related to splenomegaly and hypersplenism (a common feature of PHT).Abnormal platelet function is attributed to many causes, including intrinsic platelet defects and abnormal interaction among platelets, endothelial surfaces, and clotting factors. It is manifested by a prolonged bleeding time, impaired platelet aggregation, and reduced adhesiveness. Some authorities attribute the inhibition of platelet aggregation to fibrin degradation products (FDPs); however, the FDP levels noted in the plasma of cirrhotic patients are not sufficient to impair platelet aggregation, nor do they correlate with the observed reductions in platelet aggregation.86 Platelets should be transfused whenever a patient with either a quantitative or a qualitative defect experiences active bleeding. A normal response is a rise of 10,000/mm3 with each unit transfused; however, in cases of hypersplenism and accelerated consumption, such a response is rare.Transfusion should be continued until all serious bleeding has ceased, with the therapeutic goal being the maintenance of a platelet count near 50,000/mm3. Platelet transfusion is also indicated before any surgical or invasive procedure (e.g., paracentesis or liver biopsy). Indications for prophylactic platelet transfusion are less clear, and any potential gains must be balanced against potential side effects and development of antibodies. Most patients with advanced cirrhosis and liver failure have platelet counts lower than 100,000/mm3; however, prophylactic platelet transfusion is usually not recommended until the count falls below 15,000 to 20,000/mm3, at which point the risk of spontaneous bleeding is considerably increased. Another feature of severe liver disease is increased fibrinolytic activity, which may be either primary or secondary to DIC.87 The exact causes of primary fibrinolysis and DIC remain unclear. Primary fibrinolysis appears to derive from increased activity of tissue plasminogen activator and decreased levels of α 2-antiplasmin.88 DIC is believed to be triggered by the release of thromboplastic substances into the circulation as a consequence of liver cell damage or necrosis and by poor clearance of circulating activated tissue and clotting factors and FDPs by a defective reticuloendothelial system. Accelerated fibrinolysis is manifested by reductions in the whole blood clot lysis time and the euglobulin clot lysis time as well as by elevated levels of fibrinolysis products (e.g., FDPs and D-dimer). Although enhanced fibrinolysis is relatively common in patients with cirrhosis,

Table 11

Contraindications to Liver Transplantation

Absolute contraindications

Severe, irreversible brain damage HIV infection Extrahepatic malignancy Uncontrolled sepsis Severe pulmonary hypertension and advanced cardiopulmonary disease Active substance abuse or major psychosocial problems Extrahepatic portal vein thrombosis in patients with hepatocellular carcinoma

Relative contraindications

Elevated ICP or reduced CPP (in patients with FHF) Multiple organ dysfunction syndrome Hemodynamic instability Advanced age Portal vein thrombosis (except when secondary to hepatocellular carcinoma)

CPP—cerebral perfusion pressure

ICP—intracranial pressure

6 HEPATIC FAILURE — 14

Table 12

Child-Turcotte-Pugh Scoring System

Points

1

2

3

Encephalopathy

None

Stage I or II

Stage III or IV

Ascites

Absent

Slight (or controlled by diuretics)

Moderate despite diuretic treatment

Bilirubin (mg/dl) Patients with PBC or PSC

6

Albumin (g/L)

> 3.5

2.8–3.5

< 2.8

PT (prolonged sec) INR

6 > 2.3

PBC—primary biliary cirrhosis

PSC—primary sclerosing cholangitis

most of the characteristic abnormalities can occur after many types of physiologic stress and are not necessarily accompanied by a bleeding tendency. At present, no satisfactory method of managing DIC is available. An extensive workup must be completed to rule out underlying causes (e.g., sepsis, ARDS, and MODS). FFP, platelet concentrates, and, possibly, low-dose heparin (200 to 800 U/hr) may be given. AT-III concentrate has been used in an attempt to inhibit the action of thrombin, thereby decreasing procoagulant consumption, restoring normal levels of factors, and improving hemostasis. Clinical experience with AT-III therapy in this setting has been limited to a few case reports and a few small series; however, there is some evidence to suggest that AT-III may reduce the hemostatic abnormalities and help control bleeding.89 Antifibrinolytic agents (e.g., ε-aminocaproic acid and tranexamic acid) impede fibrinolysis and thus may be useful for treating bleeding in patients who have liver disease and show evidence of fibrinolysis.90 In patients with DIC, however, administration of antifibrinolytic agents is contraindicated because of the potential for thrombotic complications. D-dimer levels should be determined to rule out DIC before use of these medications is considered. Because DIC is difficult to rule out in patients with liver disease, the use of antifibrinolytic agents in liver disease is limited. LIVER TRANSPLANTATION

The standard indications for liver transplantation are well documented91: they include PHT, poor hepatic synthetic function, hepatic encephalopathy, progressive jaundice, severe malnutrition, and excessive fatigue. As noted [seeTreatment of Complications, above], PHT is manifested by variceal bleeding, hypersplenism, thrombocytopenia, ascites, hepatic hydrothorax, and SBP. Poor synthetic function is usually manifested by a prolonged PT and low serum albumin and cholesterol levels. In general, any concurrent medical or psychosocial condition that prohibits a major surgical procedure or subsequent immunosuppression constitutes a contraindication to liver transplantation [see Table 11]. The United Network for Organ Sharing (UNOS) currently regulates organ allocation to transplant candidates. In January 1988, minimal listing criteria for liver transplantation were implemented.92 These criteria are based on the Child-Turcotte-Pugh (CTP) scoring system [see Table 12], which includes five parameters: serum albumin

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10 HEPATIC FAILURE — 15

and bilirubin levels, PT, ascites, and hepatic encephalopathy.To be listed for liver transplantation, a patient must have a CTP score of 7 or higher. In addition to the general listing criteria, various disease-

specific criteria were developed for patients with alcoholic liver disease, patients with cholestatic liver disease (e.g., PBC or primary sclerosing cholangitis), and patients with hepatocellular carcinoma.

Discussion Mechanisms of Hepatic Encephalopathy

The association between liver disease and altered mental status and consciousness has been recognized for centuries, but the exact underlying mechanisms remain unknown. It appears that this syndrome has a multifactorial etiology and is associated with a number of complex changes, which are manifested collectively as hepatic encephalopathy. It is generally believed that hepatocerebral dysfunction is caused by accumulation of cerebral toxins as a result of low hepatic clearance.93 Of all the physiologic factors thought to contribute to the development of encephalopathy, the best known is ammonia. Arterial ammonia levels are frequently elevated in persons with hepatic encephalopathy; however, the clinical severity of hepatic encephalopathy correlates poorly with the degree to which the ammonia level is elevated.94 The precise contribution of ammonia to hepatic encephalopathy remains unclear; however, ammonia is known to inhibit the uptake of glutamate into the astrocytes, thereby causing a rise in the extracellular glutamate level that appears to downregulate the postsynaptic glutamate receptors, resulting in decreased neuronal excitation.95 Endogenous or exogenously ingested benzodiazepines may also play a role in the etiology of acute and chronic hepatic encephalopathy by interacting with the high-affinity γ-aminobutyric acid (GABA)– benzodiazepine receptor complexes.These substances are known to enhance inhibitory GABA-ergic tone. Animal studies suggest that the gut flora may contribute benzodiazepine ligand activity 96 as well as increased benzodiazepine receptor agonist activity.97 Clinical studies of FHF patients show increased benzodiazepine receptor ligands with enhanced GABA-ergic tone in all stages of encephalopathy.98 Ammonia-induced activation of peripheral-type benzodiazepine re-

Table 13

Neurologic Effects of BAL Treatment

Study Group

Results Pre-BAL

Post-BAL

P

Group I ICP (mm Hg) CPP (mm Hg) GCS CLOCS

17.0 ± 1.5 70 ± 2 6.8 ± 0.4 24.7 ± 1.2

10.9 ± 1.0 75 ± 2 7.4 ± 0.4 32.0 ± 1.1

< 0.0002 < 0.04 < 0.01 < 0.000001

Group II GCS CLOCS

5.0 ± 1.1 29.7 ± 7.4

7.0 ± 1.4 31.7 ± 7.9

< 0.2 < 0.5

Group III ICP (mm Hg) CPP (mm Hg) GCS CLOCS

12.3 ± 0.9 85 ± 1 8.2 ± 0.7 29.7 ± 2.3

14.0 ± 1.5 98 ± 8 8.4 ± 0.7 34.0 ± 1.7

< 0.4 < 0.3 < 0.4 < 0.001

BAL—bioartificial liver CLOCS—Comprehensive Level of Consciousness score CPP—cerebral perfusion pressure GCS—Glasgow Coma Scale ICP—intracranial pressure

ceptors on astrocytes may cause the release of neurosteroids that enhance GABA-ergic neurotransmission. Hence, neurosteroids may potentate the inhibitory actions of GABA at the receptor level as well as lengthen the period during which the GABA ligand remains in the synaptic cleft. Ammonia also acts directly to potentiate GABA-ergic tone by enhancing the affinity of GABA for GABA-A receptors.99 Despite these seemingly compelling findings, there is no apparent correlation between benzodiazepine ligand activity and clinical stage of encephalopathy, nor is ligand elevation a consistent finding in all patients. Furthermore, clinical and animal studies in which a benzodiazepine receptor antagonist has been administered have not shown consistent effects.The anecdotal success of flumazenil, the principal benzodiazepine antagonist, has been ascribed to the antagonism of benzodiazepines ingested by patients. Support for the concept of socalled endogenous benzodiazepines arising from the intestine can be found in a number of sources, including studies of dogs with congenital portacaval shunts, which document ligand activity in stool samples.100 Whether there is a causal relation to hepatic encephalopathy or whether this is merely a case of associated phenomena remains to be determined.Whatever the contribution of benzodiazepines to the pathophysiology of acute hepatic encephalopathy and cerebral edema, it appears likely that other mechanisms are involved. Bioartificial Liver Support System

Despite the best management efforts, the morbidity and mortality associated with ALF remain exceptionally high. For most severe cases, liver transplantation is still the only effective therapeutic modality. Unfortunately, because of the severe organ donor shortage, the waiting period for transplantation is long, and patients consequently are at risk for the development of irreversible complications or contraindications to liver transplantation while awaiting a donor. In an effort to mitigate this problem, investigators have studied various artificial liver support systems designed to provide full metabolic, hemodynamic, and physiologic support until either the native liver regenerates or a liver becomes available for transplantation. From the 1970s to the 1990s, most therapeutic attempts focused primarily on detoxifying plasma. All such attempts either failed or had no significant impact on survival.101 The ongoing severe organ shortage has led several investigators to develop and test a number of xenogeneic-based liver support systems employing whole-organ perfusion or isolated hepatocytes. At our institution, we developed and tested a hybrid bioartificial liver (BAL) support system employing isolated porcine hepatocytes in an extracorporeal perfusion circuit.We subsequently initiated a clinical trial addressing the use of this system in patients with severe ALF as a bridge to either transplantation or spontaneous recovery.102-104 CLINICAL TRIAL

Study Design Hepatocytes Methods of porcine hepatocyte isolation, purification, attachment to a collagen-coated matrix, cryopreservation,

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Table 14

10 HEPATIC FAILURE — 16

Metabolic Effects of BAL Treatment

Study Group

Results Pre-BAL

Post-BAL

P

Group I AST (U/L) ALT (U/L) Total bilirubin (mg/dl) Glucose (mg/dl) Ammonia (µmol/L) Lactate (mmol/L) Albumin (g/dl) Creatinine (mg/dl)

1,255 ± 261 1,075 ± 184 17.9 ± 1.5 126 ± 5 160 ± 8 4.4 ± 0.7 3.12 ± 0.08 1.5 ± 0.2

879 ± 148 674 ± 120 14.6 ± 1.2 175 ± 7 134 ± 6 4.2 ± 0.6 2.6 ± 0.1 1.1 ± 0.1

< 0.002 < 0.000005 < 0.000001 < 0.0000006 < 0.0002 < 0.2 < 0.0000006 < 0.000001

Group II AST (U/L) ALT (U/L) Total bilirubin (mg/dl) Glucose (mg/dl) Ammonia (µmol/L) Lactate (mmol/L) Albumin (g/dl) Creatinine (mg/dl)

5,661 ± 2,613 2,139 ± 704 19.1 ± 2.2 117 ± 26 81 ± 9 13.1 ± 2.9 3.7 ± 0.3 1.6 ± 0.3

2,821 ± 1,291 1,633 ± 544 14.7 ± 1.7 144 ± 24 91 ± 13 13.2 ± 2.2 2.7 ± 0.1 1.6 ± 0.3

< 0.1 < 0.05 < 0.009 < 0.06 < 0.03 < 0.9 < 0.01 < 1.0

Group III AST (U/L) ALT (U/L) Total bilirubin (mg/dl) Glucose (mg/dl) Ammonia (µmol/L) Lactate (mmol/L) Albumin (g/dl) Creatinine (mg/dl)

692 ± 374 349 ± 126 26.0 ± 2.7 141 ± 9 173 ± 31 5.7 ± 1.1 3.0 ± 0.1 2.8 ± 0.3

723 ± 409 281 ± 114 21.6 ± 2.2 171 ± 11 131 ± 15 5.6 ± 0.9 2.6 ± 0.1 2.2 ± 0.2

< 0.5 < 0.06 < 0.000003 < 0.001 < 0.08 < 0.9 < 0.00003 < 0.00002

ALT—alanine aminotransferase liver

cells return from the BAL, they are reconstituted and returned to the patient via the double-lumen venous dialysis catheter. Patient population Three groups of patients were enrolled in the phase 1 trial. Group I patients (N = 24) had no previous history of liver disease, fulfilled all the diagnostic criteria of FHF, and were candidates for OLT at the time of admission. Group II patients (N = 3) had undergone OLT and exhibited primary nonfunction (PNF) of the transplanted liver in the immediate postoperative period with rapid deterioration. Group III patients (N = 10) presented with acute exacerbation of known underlying chronic liver disease and were not candidates for OLT at the time of study enrollment. Patients were enrolled in the study when stage III or IV encephalopathy developed in the course of optimal standard medical therapy. Results

AST—aspartate aminotransferase

BAL—bioartificial

and storage were developed. Five to seven billion fresh or cryopreserved hepatocytes (70% to 90% viability) were used for each patient treatment.103,104 System characteristics The system was standardized and subsequently modified and is currently manufactured as the HepatAssist 2000 (Circe Biomedical, Inc., Lexington, Massachusetts).The main components are (1) a plasmapheresis unit, (2) an activated cellulosecoated charcoal column, (3) an oxygenator, (4) a blood warmer, and (5) a hollow-fiber module containing isolated microcarrier-attached porcine hepatocytes. The module consists of (a) an intracapillary chamber made of several porous, hollow 0.2 µm fibers through which plasma flows and (b) an extracapillary chamber surrounding the hollow fibers, where the microcarrier-attached hepatocytes are suspended. Plasma circulates through the fibers at a rate of 400 ml/min, with free exchange of macromolecules across the surface of the fibers driven by a transmembrane pressure gradient.When plasma and blood

Of the 24 group I patients, 18 were candidates for OLT. Five additional patients with FHF secondary to acetaminophen toxicity who were treated with the BAL support system recovered fully without the need for liver transplantation. One patient with FHF secondary to heatstroke received BAL treatment while awaiting OLT; he died as a result of MODS after 21 days. All 18 OLT candidates in group I and all three patients in group II were successfully bridged to transplantation, experienced full neurologic and functional recovery, and were discharged from the hospital. Patients in group III experienced transient clinical improvement after BAL treatment.Two patients recovered enough native liver function to survive; they subsequently became candidates for OLT and underwent the procedure successfully.The remaining eight patients died 1 to 21 days (mean, 7.1 days) after their last BAL treatment as a result of variceal bleeding, sepsis, or MODS. Treatment with the BAL support system gave rise to several neurologic and metabolic effects that were seen in all three groups of patients. Of these, the neurologic changes were the most dramatic. Patients with FHF (group I) exhibited remarkable neurologic improvement after BAL treatment, with the reversal of decerebrate posturing states, anisocoria, and sluggish pupillary reflexes. Both responsiveness to external stimuli and brain-stem function improved, as shown by a higher comprehensive level of consciousness score.There was a significant reduction in ICP with a concomitant increase in CPP; these changes were most dramatic in patients with ICP levels higher than 25 mm Hg [see Table 13]. In patients with PNF (group II), the impact of BAL treatment on neurologic status was difficult to assess because heavy sedation was used in the postanesthetic period; however, transient neurologic improvements were noted after BAL treatment, manifested primarily by increased responsiveness. Additional metabolic effects of BAL treatment on liver function included improvements in renal function and hematologic and coagulation parameters [see Table 14]. There was a significant (P < 0.01) increase in the plasma BCAA-AAA ratio in plasma, which may be one of many possible reasons for the observed mitigation of encephalopathy.This increase was primarily due to a reduction in AAA levels.

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