How do I manage a patient with acute liver failure?

70 How Do I Manage a Patient With Acute Liver Failure? Mark T. Keegan

Acute liver failure (ALF) is a catastrophic condition that can result in multiple organ failure. The severity of the illness and rapidity of clinical deterioration in a previously healthy individual is alarming to patients, their families, and the health-care team. Care of the patient with ALF requires full armamentarium of therapies available in a modern intensive care unit (ICU) and may require orthotopic liver transplantation (OLT).1 Survival rates have increased significantly in recent years, and advances in ICU management have driven improved outcomes.2–7 ALF (the preferred term) is defined as the onset of hepatic encephalopathy (HE) and coagulopathy within 26 weeks of jaundice in a patient without preexisting liver disease. Terms that base classification on the duration of illness are popular but less useful because they do not have prognostic significance distinct from the etiology.8–10 In 2011 the American Association for the Study of Liver Diseases (AASLD) updated its position paper detailing the management of ALF.11 Recommendations of the U.S. Acute Liver Failure Study Group for the ICU management of such patients were published in 2007.12 The European Association for the Study of the Liver (EASL) and the American Gastroenterological Association Institute both published guidelines on ALF in 2017.6,13 The rarity, heterogeneity, severity, and speed of progression of ALF mean that there is a paucity of randomized controlled trials (RCTs) evaluating therapies, and many interventions are empiric or based on expert opinion.

EPIDEMIOLOGY ALF is rare. In developed countries, the reported incidence is between 1 and 6 cases/million persons per year, with approximately 2000 cases/year in the United States.14–16 Rates are probably higher in locations with high rates of infective hepatitis and/or lack of resources for treatment, but data are sparse. The etiology of ALF differs depending on the geographic location. In the United States and Europe, medications are responsible for most cases.1,6 Acetaminophen accounted for 46% of the 1696 cases of adult ALF in the U.S. Acute Liver Failure Registry, many from unintentional overdose and many in women.3,17,18 In other parts of the world, a viral etiology (especially hepatitis A, B, D, and E) predominates. Other causes of ALF are detailed in Box 70.1.19 Despite the presence of a 500

preexisting liver disease, patients with an acute presentation of chronic autoimmune hepatitis, Wilson disease, and Budd– Chiari syndrome are considered as having ALF if they develop encephalopathy in the context of appropriate abnormalities in liver blood tests and coagulation profile.6

CLINICAL PRESENTATION Although ALF originates with a liver insult, it becomes a multisystem disease by inducing a three-phase (initiation, propagation, and resolution) systemic inflammatory response syndrome (SIRS). Hepatocyte death initiates a massive proinflammatory response, likely caused by activation of Kupffer cells (macrophages). This SIRS activates a compensatory antiinflammatory response.20 Systemic organ dysfunction occurs involving vasodilation, encephalopathy and cerebral edema, coagulopathy, acute kidney injury (AKI), immunosuppression, and metabolic acidosis. The stigmata of chronic liver disease are absent. HE and coagulopathy are characteristic features of ALF and may progress rapidly over days or even hours. Diagnosis of ALF is made on clinical grounds, aided by laboratory analysis. Imaging studies (e.g., hepatic ultrasound to assess the patency of the liver’s vascular supply) are usually performed. Routine liver biopsy is not advisable; although it may change the diagnosis in a minority of cases, it will usually not change therapy.13

INITIAL ASSESSMENT AND MANAGEMENT When ALF is diagnosed, a referral center with a liver transplant program should be contacted for management advice and consideration for transfer.1,3,6,11 When encephalopathy develops in a patient with ALF, ICU care is usually warranted because of the potential for further deterioration and the potential need for urgent interventions, such as intubation, mechanical ventilation, and hemodynamic support. Several institutions have developed formal protocols for management of patients with ALF.21

PROGNOSIS With supportive therapy, some patients with ALF will spontaneously recover hepatic function. In many other cases,

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BOX 70.1  Etiologies of Acute Liver Failure. Viral Hepatitis A virus, Hepatitis B virus 6 Hepatitis D virus, Hepatitis E virus, Herpes simplex virus, Cytomegalovirus, Epstein Barr virus, Varicella zoster virus, adenovirus, hemorrhagic fever viruses Drugs and Toxins Dose-dependent: Acetaminophen, carbon tetrachloride, yellow phosphorus, Amanita phalloides, Bacillus cereus toxin, sulfonamides, tetracycline, methyldioxymethamphetamine (ecstasy), herbal remedies Idiosyncratic: Volatile anesthetics (especially halothane), isoniazid, rifampicin, valproic acid, nonsteroidal antiinflammatory drugs, disulfiram Vascular Right heart failure, Budd–Chiari syndrome, veno-occlusive disease, shock liver (ischemic hepatitis), heat stroke Metabolic Acute fatty liver of pregnancy, Wilson disease, Reye syndrome, galactosemia, hereditary fructose intolerance, tyrosinemia Miscellaneous Malignant infiltration (liver metastases, lymphoma), autoimmune hepatitis, sepsis Indeterminate Includes primary graft nonfunction in liver transplant recipients Modified from Saas DA, Shakil AO. Fulminant hepatic failure. Liver Transpl. 2005;11(6):594-605.

however, the patient will die without OLT. Of 1696 patients with ALF in the U.S. Acute Liver Failure Study Group dataset, overall patient survival was 71%.3 Outcomes have improved over time. The 21-day survival rates in patient cohorts treated in 1998–2005 and 2006–2013 were 67.1 and 75.3%, respectively. Transplant-free survival improved from 45.1% during 1998–2005 to 56.2% during 2006–2013, and posttransplantation survival increased from 88.3 to 96.3%.7 Nonetheless, ALF remains a life-threatening disease entity. The main causes of death are cerebral edema with subsequent herniation and multiple organ failure. In data reported by Lee,3 660 (39%) of 1696 patients were listed for transplantation, 409 were transplanted, with 371 survivors and 38 deaths. Without transplantation, 826 survived and 461 died.3 In a 2-year follow-up, long-term survival was significantly higher in transplant recipients than in patients who survived without the need for transplantation, perhaps because of underlying comorbidities.22 The timing of transplantation is crucial. Delay in listing for transplantation may result in the patient’s demise before a donor organ is found or may result in perioperative mortality. Premature listing may result in OLT procedure in patients who might have otherwise spontaneously recovered liver function. Multiple prognostic scoring systems have been

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developed to identify patients at high risk of mortality.11,23 The most commonly used, the King’s College Criteria (KCC), were developed in a cohort of 588 patients with ALF who were managed medically between 1973 and 1985.24 The KCC differentiate between acetaminophen-induced ALF and ALF caused by other causes and use pH, international normalized ratio (INR), creatinine, encephalopathy grade, age, duration of jaundice, and bilirubin level for prognostication. These characteristics have clinically acceptable specificity but more limited sensitivity.25 Other prognostic systems include the Clichy criteria (which use encephalopathy grade, factor V concentration, and age), the Japanese criteria (age, encephalopathy grade, bilirubin level, and coagulopathy), and the ALF early dynamic model (international normalized ratio [INR], serum bilirubin, arterial ammonia, and HE).9,10,26 There are insufficient data to recommend a particular scheme.12,27 Box 70.2 identifies potentially helpful indicators of poor prognosis in patients with ALF.28 The etiology of ALF appears to be the most important factor, albeit with imperfect sensitivity and specificity. The United Network for Organ Sharing (UNOS), the donor organ allocation body in the United States, has criteria that must be satisfied before a patient may be listed as a Status IA candidate for liver transplantation (the highest priority for organ allocation). These include “ALF with a life expectancy of less than 7 days without a liver transplant” or “primary graft nonfunction, hepatic artery thrombosis, and acute Wilson disease.”

SPECIFIC CAUSES AND RELATED THERAPIES The cause of ALF has implications for both therapy and prognosis.6,11 N-acetylcysteine (NAC) is effective in the treatment of acetaminophen toxicity and an acetaminophen level should be drawn in every patient with ALF.6,11,18,29,30 Acetaminophen toxicity may be indicated by the presence of very high serum transaminases and low bilirubin levels and assays for toxicity-related serum acetaminophen-containing protein adducts. Intravenous (IV) NAC should be administered even if there is doubt regarding the timing or dose of ingestion or of the plasma acetaminophen concentration. The duration of administration is determined by clinical condition rather than by time or serum acetaminophen concentration.11,12 In addition to NAC administration, patients with known or suspected acetaminophen overdose within 4 hours of presentation should be administered activated charcoal prior to starting NAC.11 Nonacetaminophen, drug-induced hepatotoxicity is usually idiosyncratic. In acute drug toxicity, the serum aminotransaminase concentration is characteristically extremely elevated (.10,000 IU/L) and bilirubin levels may be normal. Lower transaminase levels may be seen in accidental staggered toxicity. Antibiotics (especially antituberculous medications), nonsteroidal antiinflammatory drugs, and anticonvulsants are most commonly implicated.3,31,32 There are no specific antidotes. In unexplained ALF, potential drug or toxin exposure should be investigated. In the U.S. Acute Liver Failure Study Group data, 11% patients had (nonacetaminophen)

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BOX 70.2  Potentially Helpful Indicators of

Poor Prognosisa in Patients With Acute Liver Failure.

Etiology • Idiosyncratic drug reaction • Acute hepatitis B (and other non-hepatitis A viral infections) • Autoimmune hepatitis • Mushroom poisoning • Wilson disease • Budd–Chiari syndrome • Indeterminate cause Coma grade on admission • III or IV King’s College criteria • Acetaminophen-induced ALF • Strongly consider OLT listing if arterial lactate .3.5 mmol/L after early fluid resuscitation • List for OLT if pH ,7.3 or arterial lactate .3.0 mmol/L after adequate fluid resuscitation • List for OLT if all three of the following occur within a 24-h period: grade III or IV HE, INR .6.5, creatinine .3.4 mg/dL • Nonacetaminophen-induced ALF • List for OLT if INR .6.5 and encephalopathy present (irrespective of grade) • List for OLT if encephalopathy present (irrespective of grade) and any three of the following are present: - Age ,10 or .40 yearsb - Jaundice for .7 days before development of encephalopathy† - INR 3.5 - Serum bilirubin 17 mg/dL - Unfavorable cause such as Wilson disease, idiosyncratic drug reaction, seronegative hepatitis Note that none of these factors, with the exception of Wilson disease and possibly mushroom poisoning, are either necessary or sufficient to indicate the need for immediate liver transplantation. b These criteria, in particular, have not been found to be predictive of outcome in recent analyses. ALF, acute liver failure; HE, hepatic encephalopathy; INR, international normalized ratio; OLT, orthotopic liver transplantation. From Lee WM, Stravitz RT, Larson AM. Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011. Hepatology. 2012;55(3):965-967. a

drug-induced ALF, and the entity was especially common in women and minorities.32 Transplant-free (3-week) survival was poor (27.1%), but with highly successful transplantation occurring in 42.1%; overall survival was 66.2%. Hepatitis A and B accounted for 4 and 8%, respectively, of ALF cases in the U.S. multicenter cohort.3,17 Viral hepatitis is more common elsewhere. Acute hepatitis D may cause acute liver dysfunction in a patient with preexisting hepatitis B, and hepatitis E may cause ALF in endemic areas, especially during pregnancy. Care of a patient with acute viral hepatitis is mainly supportive. Lamivudine may be of use in hepatitis B-associated ALF, although a clinical trial has not been

performed.11 Acyclovir and consideration for transplantation are recommended for cases of the (rarely seen) herpes simplex or varicella-zoster-induced ALF. ALF may develop as an acute presentation of autoimmune hepatitis and should be suspected in patients presenting with other autoimmune disorders, elevated globulin fraction, and autoantibodies.6 Corticosteroids (prednisolone starting at 40–60 mg/day) are often administered in this scenario, but steroid administration is not supported by the large retrospective analysis of Karkhanis et al.33 Transplantation may be required. Acute fatty liver of pregnancy is a rare disease that may occur in the third trimester. It resolves with delivery of the fetus. OLT has been performed for this condition but should not be necessary with early diagnosis and prompt delivery.34 HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) is also a disease of pregnancy, usually in association with preeclampsia. Prompt delivery is indicated and is usually associated with a good outcome. Wilson disease is an uncommon cause of ALF (2–3% of cases in the U.S. Acute Liver Failure Group cohort) but carries a grim prognosis without transplantation. Features include low serum ceruloplasmin, high serum and urinary copper, hemolysis, Kayser–Fleischer rings (seen on slit-lamp examination), very low serum alkaline phosphatase and uric acid, and a bilirubin (mg/dL) to alkaline phosphatase (IU/L) ratio of .2.35 Although penicillamine treatment may be used in Wilson disease, it is not recommended in the setting of ALF.36 Rather, other measures to reduce serum copper and prevent further hemolysis (e.g., plasmapheresis) should be initiated while the patient is waiting to undergo an emergent liver transplant. Patients with mushroom poisoning (the most hepatotoxic of which is Amanita phalloides) typically present with gastrointestinal symptoms. Mushroom poisoning has been treated with penicillin G, NAC, and silibinin although controlled trials have not been performed, and the latter is not available as a licensed drug in the United States.37 When ALF is caused by an acute ischemic injury or severe congestive heart failure, treatment of the underlying cause is required, and prognosis is related to the response to therapy of the inciting insult. Abdominal pain, prominent hepatomegaly, and ascites may indicate acute hepatic vein thrombosis (Budd–Chiari syndrome), which may present as ALF.38 Liver transplantation is indicated based on high survival rates in case series, provided underlying malignancy is excluded. Malignant infiltration of the liver sufficient to cause ALF is a contraindication to liver transplantation and indicates a very poor prognosis. Other conditions that may cause ALF but are not an indication for OLT include hemophagocytic lymphohistiocytosis and infections such as malaria, dengue fever, and rickettsiosis. ALF may be caused by extensive liver resection (e.g., hemihepatectomy) or vascular complications after liver surgery. Most patients recover if the resection is performed in the absence of advanced liver disease.

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HEPATIC ENCEPHALOPATHY Ammonia produced in the gut is usually converted to urea in the liver’s urea cycle. In hepatic failure, ammonia accumulates and is shunted to the systemic circulation. Hyperammonemia causes neuronal dysfunction, leading to HE, one of the hallmarks of ALF.39 In contrast to patients with chronic liver disease, the development of encephalopathy in a patient with ALF is often associated with the development of cerebral edema and elevations in intracranial pressure (ICP), with potential herniation. The correlation between arterial ammonia concentration and cerebral edema, although imperfect, is stronger in patients with ALF than in those with cirrhosis; an arterial ammonia .200 mmol/L within 24 hours of the development of grade III or IV HE is predictive of herniation.40 Encephalopathy may develop rapidly in patients with ALF. In the West Haven grading system, there are four grades of encephalopathy (Table 70.1). The grade of encephalopathy correlates with the development of cerebral edema and with outcome. For patients who become comatose, the Full Outline of Unresponsiveness or FOUR score is more discriminating because it includes brain stem and respiration assessment, which are not further differentiated in the West Haven system.41 Cerebral edema is uncommon in grade I or II, but it occurs in 25–35% and 65–75% in patients with grades III and IV encephalopathy, respectively.

Treatment of Hepatic Encephalopathy and Elevated Intracranial Pressure Grades I and II Hepatic Encephalopathy Patients with grade I HE may be managed in a general ward with skilled nursing; however, in most institutions, patients with ALF should be managed in an ICU. If and when grade II HE develops, ICU care is indicated. A computed tomography (CT) scan of the head should be performed to exclude other causes of mental status change (e.g., intracranial hemorrhage, space-occupying lesion). Although CT scans may demonstrate cerebral edema in patients with HE, intracranial hypertension may not be detected.39 Administration of sedatives to patients with grade I or II HE should be avoided if possible because they will confound

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progression detection. Nonetheless, small doses of shortacting agents (e.g., haloperidol, benzodiazepines, or dexmedetomidine) may be required to control agitation. Lactulose administration has been associated with a small increase in survival time but no difference in the severity of encephalopathy or overall outcome.42 Nonabsorbable antibiotics (rifaximin, neomycin) have also not proven to be beneficial in ALF, and neomycin carries a risk of nephrotoxicity.

Grades III and IV Hepatic Encephalopathy A patient who progresses to grade III HE requires endotracheal intubation for airway protection. There are no studies to demonstrate the advantage of one sedative or anesthetic agent over another in this circumstance. It is intuitive that a drug regimen that minimizes the risk of increasing ICP should be used, and propofol is a reasonable choice. If needed, a nondepolarizing neuromuscular blocker (e.g., cisatracurium) offers some advantages over succinylcholine in terms of its effect on ICP. Intracranial Pressure Monitoring The use of ICP monitoring devices in ALF is controversial.11,43,44 The traditionally used device, an epidural catheter, has relatively lower associated risks for intracranial hemorrhage but may be less accurate than other devices. Subdural or intraparenchymal monitors provide improved reliability but are associated with an increased risk of bleeding, and ICP monitor-associated hemorrhage may be catastrophic. Definitive recommendations for international normalized ratio (INR) or platelet count prior to ICP monitor insertion are not available. In the recent U.S. data, ICP monitoring was used in 140 (22%) of 169 patients with ALF.45,46 Hemorrhagic complications were rare. Overall 21-day mortality was similar in patients with ICP monitors (33%) and controls (38%; P 5 .24). In acetaminophen-induced ALF, no difference in 21-day mortality could be detected when comparing patients with ICP monitoring with unmonitored individuals; however, in ALF from other causes, use of ICP monitoring was associated with an increased 21-day mortality. A randomized clinical trial to determine the effectiveness of ICP monitoring in ALF would be logistically difficult and has not been performed. The AASLD position paper states that “ICP monitoring is

TABLE 70.1  Grades of Hepatic Encephalopathy. Grade

Mental Status

Tremor

EEG

I

Euphoria; occasional depression; fluctuant mild confusion; slowness of mentation and affect; untidy, slurred speech; disorder in sleep rhythm

Slight

Usually normal

II

Accentuation of grade I; drowsiness; inappropriate behavior; able to maintain sphincter control

Present (easily elicited)

Abnormal; generalized slowing

III

Sleeps most of the time but arousable; incoherent speech; marked confusion

Usually present if patient can cooperate

Always abnormal

IV

Not arousable; may or may not respond to painful stimuli

Usually absent

Always abnormal

EEG, electroencephalogram. Modified from Sass DA, Shakil AO. Fulminant hepatic failure. Gastroenterol Clin North Am. 2003;32(4):1195-1211.

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recommended in ALF patients with high-grade HE, in centers with expertise in ICP monitoring, and in patients awaiting and undergoing liver transplantation.”11 The European Guidelines advise consideration of ICP monitoring “in a highly selected subgroup of patients who have progressed to grade III or IV coma, are intubated and ventilated, and deemed to be at high risk of intracranial hemorrhage based on the presence of more than one of the following variables: a) young patients with hyperacute or acute presentations, b) ammonia level more than 150–200 µmol/L that does not drop with initial treatment intervention, c) renal impairment, and d) vasopressor support.”

Maintenance of Cerebral Perfusion Pressure The management goal for patients with cerebral edema is to limit ICP while maintaining cerebral persursion pressure (CPP). Targets for CPP are subjects of debate, but a goal ICP ,25 mm Hg and a CPP .60 mm Hg seem reasonable.11 A CPP .70 mm Hg may be of further advantage if that level can be achieved.11 An ICP .40 mm Hg and a prolonged period of time with a CPP ,50 mm Hg are strongly associated with poor neurological recovery, although the data are not sufficient to contraindicate OLT.47 It may be necessary to pharmacologically elevate mean arterial pressure (MAP) to attain and maintain a satisfactory CPP. Control of Elevations of Intracranial Pressure in Patients With Grade III or IV Hepatic Encephalopathy General Measures: Patients with elevated ICP (defined as an ICP .20–25 mm Hg for .1 minute or a CPP ,50 mm Hg) should be managed in a quiet environment with head elevated to 20–30 degrees. Obstruction to venous return (e.g., head rotation, tight endotracheal tube ties) should be avoided, endotracheal tube suctioning should be kept to a minimum, and consideration should be given to administration of a bolus of a sedative agent such as propofol or lidocaine before suctioning. Hypoxemia and hypercapnia will increase ICP, and every effort should be made to avoid these. Sedation and Analgesia: Sedation to control ICP has been recommended in patients with grade III or IV HE. Propofol is a reasonable choice.48 The induction of “barbiturate coma” with pentobarbital or sodium thiopental has been used to treat refractory intracranial hypertension in ALF, but the value of this approach is based on uncontrolled studies.49 Side effects are numerous and include hemodynamic compromise and apnea. Patients receiving infusions of propofol or barbiturates may require pressor support to maintain optimum hemodynamics. Opiate infusions are often used to treat discomfort and as adjunctive sedatives. Fentanyl is a better choice than morphine or meperidine because these two are longer acting and have active metabolites that may accumulate in hepatic or renal dysfunction. Mannitol: Mannitol is the only therapy proven in a controlled trial to reduce intracranial hypertension and improve survival in patients with ALF. Canalese et al.50 randomized 44 patients with ALF to receive mannitol (1 g/kg as required), dexamethasone (32 mg IV, then 8 mg IV every 6 hours), both

drugs, or neither drug for the treatment of elevated ICP.50 The EASL guidelines recommend a bolus of 50 mL of 20% mannitol to be administered over 20 minutes. Limitations to the use of mannitol include the development of acute renal failure or hyperosmolality (serum osmolality .320 mOsm/L). The prophylactic administration of mannitol in ALF has not been studied. Hypertonic Saline: Hypertonic saline, administered to maintain serum sodium concentrations between 145 and 155 mEq/L in patients with ALF and encephalopathy, reduced the incidence and severity of intracranial hypertension but not survival.51 The role of prophylactic hypertonic saline remains unproven, but its use is recommended by the AASLD “in patients at highest risk of developing cerebral edema.”11 The EASL guidelines recommend that mannitol or hypertonic saline be administered for surges in ICP. Hypotonic solutions and hyponatremia should be avoided because of the risk of worsening cerebral edema. Treatment of Fever: Fever exacerbates intracranial hypertension, and measures to maintain normothermia, including cooling blankets and fans, should be used in the febrile patient. Nonsteroidal antiinflammatory drugs and acetaminophen are relatively contraindicated because of the potential for nephrotoxicity and further hepatotoxicity.1,52 Hyperventilation: Hyperventilation to a partial pressure of carbon dioxide in arterial blood (PaCO2) of ,30 mm Hg causes cerebral vasoconstriction and rapidly reduces ICP in patients with cerebral edema. Prophylactic hyperventilation, however, did not reduce the incidence of cerebral edema in an RCT of 20 patients with ALF.53 Furthermore, marked hypocapnia (to a PaCO2 #25 mm Hg) or sustained hypocapnia may cause cerebral ischemia. Accordingly, the use of therapeutic hyperventilation is reserved for situations in which life-threatening cerebral edema is present and has proven refractory to other measures. Use of hyperventilation in this circumstance should be temporary for at most a few hours.11 Maintenance of PaCO2 between 30 and 40 mm Hg is a reasonable goal.12 Seizure Prophylaxis: The development of seizures will markedly increase cerebral oxygen requirements, increase ICP, and may cause or worsen cerebral edema. Subclinical seizure activity was noted in 30% of patients with ALF.54 Phenytoin administration is recommended for control of seizures when they occur, although supporting data are scarce.11 Benzodiazepines may also be administered for both their antiseizure and sedative properties, but their metabolism and clearance are greatly decreased in liver failure. Prophylactic IV phenytoin was shown to reduce the incidence of seizures in a group of 42 patients; however, the beneficial effects of phenytoin could not be documented in a confirmatory study.55 The use of prophylactic phenytoin is not supported by current evidence. Electroencephalography should be performed in grade III or IV HE if myoclonus is present, if a sudden unexplained deterioration in neurologic status occurs, or when barbiturate coma is being used for management of cerebral edema.12,55 Indomethacin: Tofteng and Larsen56 administered bolus doses of indomethacin to a series of 12 patients with

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ALF and cerebral edema and demonstrated a reduction in ICP and an increase in CPP, but further studies have not been forthcoming. Other agents: Nonabsorbable disaccharides, benzodiazepine receptor antagonists, or dopaminergic agonists have not been proven to be beneficial for the treatment of HE, nor has l-ornithine l-aspartate (LOLA), a drug that is supposed to facilitate the detoxification and excretion of ammonia.

COAGULOPATHY The development of coagulopathy is a hallmark of ALF. Coagulopathy may be due to platelet dysfunction (quantitative and qualitative), hypofibrinogenemia, and inadequate coagulation factor synthesis. Overall hemostasis, however, may be preserved by compensatory mechanisms despite marked elevation of INR and a rebalancing of coagulation may actually be slightly biased toward thrombosis.57 The thromboelastogram to aid in the management of coagulopathy (especially in patients undergoing OLT) has been shown to decrease transfusions.58,59 In the absence of bleeding, administration of fresh frozen plasma (FFP) is not required and may confound assessment of disease progression.11 Indeed, almost 40 years ago, Gazzard et al.60 showed that FFP administration did not reduce morbidity or mortality in ALF. Spontaneous and postprocedure bleeding complications are actually uncommon in patients with ALF. Nonetheless, such complications, especially in the setting of ICP monitor placement, may be catastrophic. When invasive procedures are planned or when the patient is bleeding, it may be appropriate to treat coagulopathy, although a more conservative approach to transfusion is now encouraged.11,12,58 Many clinicians advocate treatment of extreme coagulopathy (e.g., INR .7), even if invasive procedures are not planned.11 Vitamin K is typically given to patients with ALF because some have subclinical vitamin K deficiency at the time of presentation. In the absence of bleeding or plans for invasive procedures, a platelet count of greater than 10–20 3 109/L seems acceptable. If invasive procedures are planned, a platelet count of at least 50 3 109/L has been recommended. Cryoprecipitate administration has been recommended when the fibrinogen level is ,100 mg/dL. Recombinant factor VIIa (40 µg/kg) transiently corrected the coagulopathy of ALF and allowed performance of invasive procedures in two nonrandomized studies in a total of 26 patients who met KCC for liver transplantation.61 Thrombosis is a potential side effect. The use of prothrombin complex concentrates has yet to be sufficiently investigated in patients with ALF.

INFECTION Individuals with ALF are at risk for bacterial and fungal infection. Gram-positive cocci, enteric gram-negative bacilli, and Candida species are the most commonly isolated organisms. Disseminated infection may be a contraindication to transplantation. Prophylactic antimicrobial therapy may reduce the incidence of infection in ALF but does not impact

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survival, nor does antimicrobial therapy alter the relationship between SIRS and encephalopathy.62 Surveillance for infection is empirically recommended in patients with ALF.11 Antibiotics have been empirically recommended when surveillance cultures reveal significant isolates, in grade III or IV HE, in the presence of refractory hypotension, and if SIRS is present.12 Broad-spectrum antibacterial agents are typically used and vancomycin added if intravascular catheter-related bloodstream infection or methicillin-resistant Staphylococcus aureus infection is suspected.

ACUTE KIDNEY INJURY In one cohort of 1604 patients with ALF, 70% developed acute kidney injury and 30% underwent renal replacement therapy (RRT).63 AKI affected short- and long-term outcomes, but it rarely resulted in chronic kidney disease (only 4% of survivors were dialysis-dependent). Early initiation of RRT should be considered in patients with ALF, especially in those with markedly elevated ammonia, significant acidosis, and progressive HE.6 Continuous RRT (CRRT) is associated with less hemodynamic compromise and is less likely to provoke an elevation in ICP or pulmonary pressures than is intermittent dialysis, and it is the dialysis method of choice in patients with ALF.6,64 CRRT may be continued in the operating room during liver transplantation.65

HEMODYNAMIC SUPPORT Patients with ALF often develop distributive shock. Hypovolemia usually reflects transudation of fluid into the extravascular space and decreased oral intake. Despite adequate fluid resuscitation, a low systemic vascular resistance in ALF often results in persistent hypotension, and vasopressors may be required. The recommended goal MAP is 75 mm Hg, but this is not supported by data, and there are no data evaluating the need for higher pressures to augment CPP or lower pressures to reduce ICP.11,66 Similarly, there are no definitive trials to identify the best vasoactive agent to augment blood pressure. Most centers use norepinephrine, which can minimize tachycardia while preserving splanchnic (thereby hepatic) blood flow.11,66 Vasopressin use is controversial, and a small study of terlipressin in ALF (six patients with ALF and HE) at a dose that did not alter systemic hemodynamics demonstrated worsening of cerebral hyperemia and intracranial hypertension.67 Adrenal insufficiency may be present in patients with liver failure. Some data support the use of corticosteroids (e.g., hydrocortisone 200 mg/day) for refractory hypotension in patients with chronic liver failure; however, significant controversy exists regarding steroid supplementation in patients with ALF and, indeed, in all critically ill patients.68

MECHANICAL VENTILATION Intubation is indicated when ALF with grade III hepatic encephalopathy placed patients at risk for aspiration. Mechanical ventilation may be used to correct respiratory failure or severe

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metabolic acidosis. Acute respiratory distress syndrome has been reported in association with ALF. The use of lungprotective ventilation may be at odds with the need for relative respiratory alkalosis to manage elevated ICP. Therefore the use of permissive hypercapnia should be avoided. Obstruction of hepatic venous outflow by positive end-expiratory pressure (PEEP) is of theoretical concern and should not prevent the use of PEEP to aid in oxygenation and recruitment.69

GASTROINTESTINAL BLEEDING There is a significant risk of gastrointestinal bleeding in individuals with ALF, although this risk is presumably less than that in patients with cirrhosis, portal hypertension, and esophageal or gastric varices. In two controlled trials involving 75 patients, H2 blockers, but not antacids, were associated with a decreased incidence of bleeding in patients with ALF. Accordingly, H2 blockers or, by extension, proton pump inhibitors may be administered to patients with ALF.11,70

METABOLIC CONCERNS Severe metabolic acidosis is common in patients with ALF, especially when accompanied by acute renal failure. Infusions of sodium bicarbonate or a nonsodium buffer such as tris(hydroxymethyl) aminomethane or initiation of CRRT with a bicarbonate-rich infusate have been used, but evidence supporting this practice is limited. Lactic acidosis may result from a combination of hypoperfusion and decreased lactate clearance. Profound hypoglycemia secondary to impaired hepatic gluconeogenesis can occur. Boluses of 50% dextrose solutions and continuous 10% dextrose infusions have been administered to maintain normoglycemia; however, bolus administration carries a risk of osmotic shifts that may contribute to cerebral edema and intracranial hypertension. Phosphate and magnesium levels may be low. Hypophosphatemia is a favorable prognostic sign and appears to be associated with liver regeneration.71 Fluid resuscitation and, if necessary, hypertonic saline solutions should be targeted to maintain serum sodium at 140–145 mEq/L, although rapid changes in sodium should be avoided.6

NUTRITION Patients with ALF are catabolic with increased energy requirements;72 however, studies on the value of nutritional support are limited. The enteral route has been recommended although studies comparing enteral and parenteral nutrition are inconclusive. A European study of nutritional support in patients with ALF demonstrated that 25 of 33 responding units used parenteral nutrition.73 The AASLD position paper recommends 60 g of protein per day, but this does not account for patient body habitus or age; requirements determined on a g/kg basis seem more appropriate.11 Studies on the beneficial effect of branched-chain amino acids in ALF are equivocal.74 Lipid emulsions appear to be safe in patients with ALF; however, there is a moderate risk of pancreatitis.

TRANSPLANTATION Although ALF may resolve with only supportive interventions, especially in patients with acetaminophen-induced ALF, OLT is the only definitive therapy for the condition. The therapy has not been evaluated in a prospective clinical trial for patients with ALF, but there is little doubt as to its effectiveness. Overall survival for patients with ALF has increased from 15% in the pretransplant era to 60% in the posttransplant era.17 Some of the improved survival rates reflect improvements in ICU management that have also enhanced spontaneous survival rates. ALF is the only condition designated as UNOS Status I (highest priority for donor liver allocation). OLT is not universally available, and only 8–10% of liver transplantations are performed in patients with ALF.6,75,76 In the U.S. Acute Liver Failure Study Group series, 29% of patients underwent OLT and 25% of patients listed for transplantation died on the waiting list.17 A “look-back” study of adult patients admitted to the King’s College liver center in London between 1973 and 2008 demonstrated that 387 (18%) of 2095 patients with ALF underwent OLT.2 In the Nordic countries’ experience, 73% of 315 patients listed received a transplant, and 16% died without transplant.15 Mortality after OLT in the first year is higher for patients with ALF than for patients transplanted for other reasons (1-year survival rate was 79% for OLT in setting of ALF vs. approximately 90% for other causes), and most deaths occur from infection within the first 3 months.76 Outcome is worse for older recipients, those who receive older or partial grafts, and those receiving non-ABO identical grafts.76,77 Longer-term survival, however, is better than in those transplanted for chronic liver disease. Perioperative management of liver transplant patients is beyond the scope of this chapter.

AREAS OF CONTROVERSY Therapeutic Hypothermia Hypothermia (cooling to core temperature of 33°C–34°C) to decrease brain edema has been used as a “bridge to transplant” or to control ICP during transplant surgery in small series.78,79 A multicenter retrospective cohort study evaluating the impact of mild-moderate hypothermia on the prevention of elevations in ICP and the occurrence of transplant-free survival in high-risk patients with ALF and grade III-IV HE was unable to demonstrate an effect on 21-day survival or transplant-free interval.80 A multicenter RCT of prophylactic hypothermia (34°C for 72 hours) in 43 patients with ALF at high risk of cerebral edema was terminated early owing to futility.81 Adverse effects of therapeutic hypothermia appear to relate closely to the minimum temperatures achieved and include sepsis and arrhythmias. Theoretical concerns with worsening of coagulopathy and reduction in hepatic regeneration have not been seen in the ALF hypothermia trials. Hypothermia cannot be recommended as a routine management strategy for patients with ALF, though the EASL guidelines state that “mild hypothermia…. may be considered in uncontrolled intracranial hypertension.”

CHAPTER 70

N-acetylcysteine for NonacetaminophenInduced ALF NAC may have a role in nonacetaminophen-induced ALF; however, the supporting evidence is weak at this time. In a randomized, double-blind, multicenter, placebo-controlled trial, IV NAC improved transplant-free survival in patients with early-stage nonacetaminophen-induced ALF, although patients with advanced coma grades did not benefit.82 Other evidence is observational;83 however, the most recent guidelines from the American Gastroenterological Institute, presumably on the basis of sparse or inconclusive data, provided “No recommendation” for the use of NAC in nonacetaminophen ALF.

Hepatectomy and Auxiliary Transplantation The use of hepatectomy to decrease liver-derived proinflammatory cytokines has been advocated in patients with ALF, refractory circulatory dysfunction, and intracranial hypertension, assuming that OLT will be performed thereafter.84 Data to support such a practice, however, are sparse and consist of case reports and uncontrolled case series. Hepatectomy cannot be recommended at this time. Auxiliary liver transplantation is a technique in which a partial liver graft is placed either heterotopically or orthotopically while leaving part of the native liver in situ in the hope that the native liver will regenerate. If the native liver does regenerate, immunosuppression can be withdrawn, allowing the transplanted liver to atrophy. A European multicenter study demonstrated the feasibility and potential utility of this technique, but there are considerable technical difficulties.85 Subtotal hepatectomy and auxiliary liver transplantation have been performed for acetaminophen-induced ALF with encouraging early results in nonrandomized case series.86 At this time, no clear indications for auxiliary liver transplantation exist, and a randomized clinical trial has not been performed.6

Liver Support Systems The “holy grail” for the treatment of ALF is a liver support device to replace the detoxification, metabolic, and synthetic functions of the liver.87 Such a system could be used as a bridge to liver transplantation or preferably to complete

507

recovery of the patient’s native liver. Trials for the assessment of liver support devices are complicated by the fact that many patients are diverted to liver transplantation before the response to therapy with the device can be established. “Bioartificial livers” have been developed using hepatocytes harvested from pigs or derived from human hepatocellular cancer cells. A randomized, clinical trial evaluating a porcine bioartificial liver in 171 patients with ALF failed to demonstrate a survival benefit.88 Metaanalyses (based on few subjects) evaluating the utility of artificial liver support systems in ALF have provided conflicting results.89,90 A new generation of biological devices will begin clinical trials soon. “Non-biologic” systems combine hemodialysis with adsorption to albumin or charcoal. Use of commercially available artificial systems based on albumin dialysis (Molecular Adsorbent Recirculating System or MARS) and fractionated plasma separation and adsorption (Prometheus) has not been associated with improved survival, although most studies have been in patients with acute or chronic liver failure.91 A single study examining treatment with high-volume plasma exchange identified an association with increased transplantfree survival.92 Further investigations are awaited.

SUMMARY ALF is a complex, multisystem illness that develops after a catastrophic hepatic insult. It is characterized by coagulopathy and HE accompanied by cerebral edema and elevated ICP. The etiology is dependent on geographic location, with drugs and toxins causing more than half of the cases in developed countries. Care of the patient requires a multidisciplinary approach and full armamentarium of ICU support (Tables 70.2 and 70.3). The rarity of the condition and the rapidity of its development mean that there is a paucity of randomized clinical trials evaluating therapies. The U.S. Acute Liver Failure Study Group has published a consensus document with recommendations for specific aspects of ICU care of these patients, and the EASL has also published clinical practical guidelines. Although some patients recover spontaneously, for patients with poor prognosis, liver transplantation is the only definitive treatment. Survival rates after liver transplantation are approximately 75–90%. The efficacy of artificial liver support devices in ALF remains unproven.

TABLE 70.2  Important Summary Documents and Guidelines for the Management of Acute

Liver Failure. Authors

Year

Organization

Type of Document

Lee et al.

2012

American Association for the Study of Liver Diseases

Position paper on the management of acute liver failure: Update

Stravitz et al.

2007

United States Acute Liver Failure Study Group

Recommendations for intensive care of patients with acute liver failure

Wendon et al.

2017

European Association for the Study of the Liver

Clinical practice guidelines on the management of acute (fulminant) liver failure

Flamm et al

2017

American Gastroenterological Association Institute

Guidelines for the diagnosis and management of acute liver failure

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TABLE 70.3  Selected Randomized Studies in the Management of Acute Liver Failure.

Study, Year

Number of Subjects (Intervention, No Intervention)

Study Design

Intervention

Control

Outcomes

Canalese et al. 1982

44 patients with ALF (4 groups)

Prospective, randomized, controlled trial

Dexamethasone alone, mannitol alone, both dexamethasone and mannitol

Neither

Dexamethasone did not affect survival among patients who developed cerebral edema, survival was better in mannitol group

Bhatia et al. 2004

42 patients with ALF (22 patients given prophylactic phenytoin, 22 controls)

Prospective, randomized, controlled trial

Prophylactic phenytoin administration

Usual therapy

Similar rates of cerebral edema, need for mechanical ventilation, incidence of seizures, mortality

Gazzard et al. 1975

20 patients with acetaminopheninduced ALF (10 intervention, 10 controls)

Prospective, randomized, controlled trial

FFP 300 mL every 6h

Usual therapy

No difference in morbidity or mortality between intervention and control groups

Davenport et al. 1993

32 patients (12 intermittent RRT, 20 continuous RRT)

Prospective, randomized, controlled trial of patients with ALF and acute renal failure

Continuous RRT

Intermittent RRT

Patients in intermittent RRT had significantly lower cardiac indices and MAP

Demetriou et al. 2004

171 patients (85 bioartificial liver, 86 control)

Prospective, randomized, controlled, multicenter trial in patients with severe ALF

HepatAssist bioartificial liver (patients were allowed to undergo liver transplantation)

Usual therapy 30-day survival 71% (including for bioartificial liver potential liver vs. 62% for control transplantation) (P 5 .26).

Acharya et al. 2009

201 patients

Prospective, randomized, placebo-controlled, trial in patients with ALF

LOLA infusions (30 g daily over 3 days) HepatAssist bioartificial liver (patients were allowed to undergo liver transplantation)

Placebo

Bernal et al. 2016

43 patients with ALF (17 in the hypothermia group, 26 in the control group)

Prospective, randomized, controlled, multicenter trial in patients with ALF, HE and ICP monitoring

Targeted temperature management to 34°C for 72 h

Targeted No significant temperature difference between management to the groups in the 36°C for 72 h prevention of intracranial hemorrhage or in overall survival

Lee et al. 2009

173 patients with ALF (81 received N-acetyl cysteine, 92 received placebo)

Randomized, double-blind, multicenter placebo controlled trial in patients with non-acetaminophen-related ALF

Intravenous N-acetyl cysteine infusion for 72 h

Placebo

No improvement in encephalopathy grade or survival with LOLA administration

Improved transplantfree survival at 3 weeks in patients with early-stage ALF but not in those with advanced HE.

ALF, acute liver failure; FFP, fresh frozen plasma; HE, hepatic encephalopathy; LOLA, l-ornithine l-aspartate; MAP, mean arterial pressure; RRT, renal replacement therapy.

CHAPTER 70

AUTHOR’S RECOMMENDATIONS • The diagnosis of ALF should prompt discussion with a referral center for consideration of transfer and potential liver transplantation. • The U.S. Acute Liver Failure Study Group and the European Association for the Study of the Liver have both published recommendations for the management of patients with ALF. • The cause of ALF should be determined because specific therapies exist for certain conditions. Acetaminophen overdose is a common cause of ALF and should be treated with NAC. The utility of NAC in non-acetaminophen ALF remains controversial • Use of ICP monitoring has not been demonstrated to improve mortality in patients with ALF; however, some centers empirically target an ICP ,25 mm Hg and a CPP .60 mm Hg. • Coagulopathy should be treated only if invasive procedures are planned, if the patient is actively bleeding, or if the coagulopathy is extreme. • Transplantation is the only definitive treatment for ALF, and, provided there are no contraindications, the patient should receive a highest priority listing for liver transplantation.

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55. Bhatia V, Batra Y, Acharya SK. Prophylactic phenytoin does not improve cerebral edema or survival in acute liver failure—a controlled clinical trial. J Hepatol. 2004;41(1):89-96. 56. Tofteng F, Larsen FS. The effect of indomethacin on intracranial pressure, cerebral perfusion and extracellular lactate and glutamate concentrations in patients with fulminant hepatic failure. J Cereb Blood Flow Metab. 2004;24(7):798-804. 57. Stravitz RT, Lisman T, Luketic VA, et al. Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography. J Hepatol. 2012;56(1):129-136. 58. De Pietri L, Bianchini M, Montalti R, et al. Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: a randomized, controlled trial. Hepatology. 2016;63(2):566-573. 59. Wang SC, Shieh JF, Chang KY, et al. Thromboelastographyguided transfusion decreases intraoperative blood transfusion during orthotopic liver transplantation: randomized clinical trial. Transplant Proc. 2010;42(7):2590-2593. 60. Gazzard BG, Henderson JM, Williams R. Early changes in coagulation following a paracetamol overdose and a controlled trial of fresh frozen plasma therapy. Gut. 1975;16(8): 617-620. 61. Shami VM, Caldwell SH, Hespenheide EE, Arseneau KO, Bickston SJ, Macik BG. Recombinant activated factor VII for coagulopathy in fulminant hepatic failure compared with conventional therapy. Liver Transpl. 2003;9(2):138-143. 62. Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology. 2000;32(4 Pt 1):734-739. 63. Tujios SR, Hynan LS, Vazquez MA, et al. Risk factors and outcomes of acute kidney injury in patients with acute liver failure. Clin Gastroenterol Hepatol. 2015;13(2):352-359. 64. Davenport A. Renal replacement therapy in the patient with acute brain injury. Am J Kidney Dis. 2001;37(3):457-466. 65. Nadim MK, Annanthapanyasut W, Matsuoka L, et al. Intraoperative hemodialysis during liver transplantation: a decade of experience. Liver Transpl. 2014;20(7):756-764. 66. Stravitz RT, Kramer DJ. Management of acute liver failure. Nat Rev Gastroenterol Hepatol. 2009;6(9):542-553. 67. Shawcross DL, Davies NA, Mookerjee RP, et al. Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy. Hepatology. 2004; 39(2):471-475. 68. Marik PE. Adrenal-exhaustion syndrome in patients with liver disease. Intensive Care Med. 2006;32(2):275-280. 69. Saner FH, Olde Damink SW, Pavlakoviƒá G, et al. Positive endexpiratory pressure induces liver congestion in living donor liver transplant patients: myth or fact. Transplantation. 2008; 85(12):1863-1866. 70. Macdougall BR, Bailey RJ, Williams R. H2-receptor antagonists and antacids in the prevention of acute gastrointestinal haemorrhage in fulminant hepatic failure. Two controlled trials. Lancet. 1977;1(8012):617-619. 71. Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology. 2002;36(3):659-665. 72. Walsh TS, Wigmore SJ, Hopton P, Richardson R, Lee A. Energy expenditure in acetaminophen-induced fulminant hepatic failure. Crit Care Med. 2000;28(3):649-654. 73. Schütz T, Bechstein WO, Neuhaus P, Lochs H, Plauth M. Clinical practice of nutrition in acute liver failure—a European survey. Clin Nutr. 2004;23(5):975-982.

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e1 Abstract: Acute liver failure (ALF) is a complex, multisystem illness that develops after a catastrophic hepatic insult. It is characterized by coagulopathy and hepatic encephalopathy accompanied by cerebral edema and elevated intracranial pressure (ICP). The etiology is dependent on geographic location, with drugs and toxins being responsible for the majority of the cases in developed countries. Care of the patient requires a multidisciplinary approach and full armamentarium of intensive care unit (ICU) support. The rarity of the condition and the rapidity of its development mean that there is a paucity of randomized clinical trials evaluating therapies for ALF. The U.S. Acute

Liver Failure Study Group has published a consensus document with recommendations for specific aspects of ICU care of these patients and the European Association for the Study of the Liver has also published clinical practice guidelines. Although some patients recover spontaneously, liver transplantation is the only definitive treatment for patients with poor prognosis. Survival rates after liver transplantation are approximately 75–90%. The efficacy of artificial liver support devices in ALF remains unproven. Keywords: acute liver failure, fulminant hepatic failure, hepatic encephalopathy, intensive care unit, liver disease, liver support.