Management of hepatic encephalopathy.

Curr Treat Options Neurol (2014) 16:297 DOI 10.1007/s11940-014-0297-2

NEUROLOGIC MANIFESTATIONS OF SYSTEMIC DISEASE (A PRUITT, SECTION EDITOR)

Management of Hepatic Encephalopathy Jennifer A. Frontera, MD, FNCS1,2,3,* Address 1 Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA *,2Cerebrovascular Center, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA Email: [email protected] 3 Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, OH, USA * Springer Science+Business Media New York 2014

This article is part of the Topical Collection on Neurologic Manifestations of Systemic Disease Keywords Hepatic encephalopathy I Management Hyponatremia I Chronic liver disease I Prognosis

I

Treatment

I

Intracranial pressure

I

Blood ammonia

I

Opinion statement Hepatic encephalopathy management varies depending on the acuity of liver failure. However, in patients with either acute or chronic liver failure five basic steps in management are critical: stabilization, addressing modifiable precipitating factors, lowering blood ammonia, managing elevated intracranial pressure (ICP) (if present), and managing complications of liver failure that can contribute to encephalopathy, particularly hyponatremia. Because liver failure patients are prone to a variety of other medical problems that can lead to encephalopathy (such as coagulopathy associated intracranial hemorrhage, electrolyte disarray, renal failure, hypotension, hypoglycemia, and infection), a thorough history, physical and neurologic examination is mandated in all encephalopathic liver failure patients. There should be a low threshold for brain imaging in patients with focal neurological deficits given the propensity for spontaneous intracranial hemorrhage. In patients with acute liver failure and high grade encephalopathy, identification of the etiology of acute liver failure is essential to guide treatment and antidote administration, particularly in the case of acetaminophen poisoning. Equally critical is management of elevated ICP in acute liver failure. Intracranial hypertension can be treated with hypertonic saline and/or adjustment of the dialysis bath. Placement of an intracranial monitor to guide ICP therapy is risky because of concomitant coagulopathy and remains controversial. Continuous renal replacement therapy may help lower serum ammonia, treat coexisting uremia, and improve symptoms. Liver transplantation is the definitive treatment for patients with acute liver failure and hepatic encephalopathy. In patients with chronic hepatic encephalopathy, lactulose and rifaxamin remain a mainstay of therapy. In these patients, it is essential to identify reversible causes of hepatic encephalopathy such as increased ammonia production and/or decreased clearance (eg, infection, GI bleed, constipation, hypokalemia, dehydration). Chronic hyponatremia should be managed by gradual sodium correction of

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Curr Treat Options Neurol (2014) 16:297

no more than 8 12 meq/L per day to avoid central myelinolysis syndrome. Free water restriction and increased dietary sodium are reasonable, cost effective treatment options. Many emerging therapies, both pharmacologic and interventional, are currently being studied to improve management of hepatic encephalopathy.

Introduction Hepatic encephalopathy (HE) is characterized by reversible neurologic and psychiatric abnormalities in attentiveness, cognition, sleep, coordination, extrapyramidal function, mood, or behavior. Hepatic encephalopathy can occur in the context of acute liver failure (type A), portal-systemic bypass without hepatocellular disease (type B), and in cirrhosis and portal hypertension (type C) [1]. HE is generally classified as overt (with obvious symptoms) or minimal (subtle symptoms appreciable on neuropsychiatric testing) and further characterized as episodic, recurrent (more than one episode within

6 months), or persistent. Though HE is typically broken down into five grades (West Haven Criteria [1], Table 1), there is a spectrum of neurocognitive impairment ranging from mild psychometric deficits to overt coma [2]. Overt HE (stages 1 4) occurs in 30 % 45 % of cirrhotics and 10 % 50 % of those with transjugular intrahepatic portal-systemic shunts [3, 4]. Minimal HE (stage 0), characterized by deficits in short-term memory, attention and executive function, occurs in up to 84 % of patients with cirrhosis and is typically detected by detailed neuropsychiatric batteries [5–7].

Pathophysiology of hepatic encephalopathy HE is thought to be primarily because of ammonia-induced neurotoxicity and excessive GABAnergic inhibitory neurotransmitter activity. Ammonia produced either by catabolism of nitrogenous sources or by glutamine metabolism at a mitochondrial level, has been shown to lead to astrocyte swelling and dysfunction [8]. Metabolism of glutamine into ammonia and glutamate may additionally cause stimulation of N-methyl-Daspartate receptor (NMDA) receptors triggering nitric oxide release and subsequent vasodilation. This vasodilation may lead to hyperemia and cerebral edema [9]. In addition, cerebral autoregulation has been found to be impaired in patients with acute hepatic failure [10–12]. A variety

Table 1. Hepatic encephalopathy grade Grade

Level of consciousness/ cognitive function

Neurologic function

Psychiatric symptoms

0 1

Mild psychometric abnormalities Mild confusion, impaired computations, sleep disturbance, Moderate confusion, inattentive, disorientation to time Completely disoriented, marked confusion, lethargic, but arousable command following Noncommand following coma

Normal Incoordination, tremor, ±asterixis

Normal or mild mood disorder Euphoria/depression

Slurred speech, impaired handwriting, asterixis

Personality changes, irritability, decreased inhibitions Inappropriate or bizarre behavior, anxiety or apathy paranoia, anger, or rage Coma

2 3

4

Slurred speech asterixis nystagmus hypo- or hyperactive reflexes, ataxia Dilated pupils, loss of cranial nerve reflexes, signs of herniation, flexor or extensor posturing loss of reflexes


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of other mechanisms may be involved in the pathogenesis of HE including catecholamine and other neurotransmitter abnormalities, and activation of the aquaporin-4 water channel protein on astrocytes. Inflammation may also play a role because elevated TNFa levels have been documented in patients with elevated ICP compared with those without [13].

Examination findings Neurologic examination findings in hepatic encephalopathy are listed in Table 2. It should be noted that patients with liver disease are prone to other neurologic complications such as coagulopathy associated intracranial hemorrhage, hepatic myelopathy, extrapyramidal rigidity and tremor (Wilson disease), alcoholic neuropathy, cerebellar atrophy, or alcohol-related seizure disorder [2]. Focal neurologic signs should prompt a diagnostic evaluation, but have been described in the context HE with normal computed tomography (CT), electroencephalogram (EEG), magnetic resonance imaging (MRI), and CSF studies

Table 2. Neurologic examination findings in hepatic encephalopathy (listed from least to most severe) Examination components

Examination findings

Neurologic examination Mental status Abnormal neuropsychometric testing Impaired executive function Impaired short-term memory Impaired computations Inattentiveness Disorientation Lethargy No command following Coma Cranial nerves Nystagmus Dilated pupils Motor Tremor Asterixis Impaired handwriting Increased tone Hemiplegia has been described (14) Flexor posturing Extensor posturing Opisthotonos Sensory Hemisensory changes have been described [14] Cerebellar Incoordination Dysarthria Ataxia Reflexes Hypo or hyperactive reflexes Babinski sign Clonus

Corresponding encephalopathy grade 0 0 0 1 2 2 3 4 4 3 4 1 2 2 4 3 4 4 4 3 1 2 3 3 4 4

or minimal hepatic encephalopathy or minimal hepatic encephalopathy or minimal hepatic encephalopathy

or 3

or 3

or 4

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Curr Treat Options Neurol (2014) 16:297 [14]. General examination findings related to chronic liver disease may be present including jaundice, scleral icterus, ascites, palmar erythema, spider angiomata, anasarca, and fetor hepaticus. Kayer-Fleisher rings may be seen on slitlamp examination in patients with Wilson disease.

Diagnostic considerations It is important to determine the etiology of acute liver failure as soon as possible. Suggested imaging and laboratory studies are listed in Table 3. Laboratory tests can confirm the diagnosis of viral, infectious, and autoimmune causes of acute liver failure. In the absence of specialized laboratory data, a great deal of information can be garnered from basic liver function tests. A bilirubin to alkaline phosphatase ratio exceeding 2.0 can signal Wilson disease [15] and transaminitis in the context of low or normal bilirubin typically indicates acetaminophen toxicity or ischemic/hypoxic injury [16•]. Imaging studies such as ultrasound or abdominal CT may provide clues to biliary tract obstruction, infiltrative hepatopathy, tumor, hepatic vein obstruction, or acute exacerbation of chronic liver disease. Nonprimary hepatic disease, such as sepsis, hemolytic crisis, and acute pericardial constriction, may mimic acute liver failure if coagulation abnormalities, hyperbilirubinemia, or transaminitis are prominent. Warfarin ingestion and consumptive coagulopathy must be considered when isolated coagulopathy is present. Patients with high grade encephalopathy (III/IV) and any patient with an acute deterioration in mental status or focal findings on examination should undergo a noncontrast head CT to assess for intracranial hemorrhage or cerebral edema [17]. It should be noted, however, that elevated ICP can occur in the context of a normal head CT [18, 19]. In addition to a baseline CT, a head CT should be performed after insertion or removal of an ICP monitor to check for hemorrhage and device positioning. Though MRI may detect cerebral edema with more sensitivity and specificity than CT, the risks of transport and the time involved in obtaining an MRI may outweigh the benefits in diagnostic accuracy.

Treatment Treatment strategies for HE vary depending on the level of acuity of liver failure and the degree of neurologic impairment. Patients with acute liver failure may need management specific to the acute cause of liver failure and are at high risk for elevated ICP. Acute liver failure is standardly defined by an INR ≥1.5 , and encephalopathy with liver failure G26 weeks duration without pre-existing cirrhosis [16•]. These patients often require intensive medical treatment and monitoring for ICP control. An overview of the 2011 guidelines for the management of acute liver failure from the American Association for the Study of Liver Dis-


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Table 3. Laboratory and imaging evaluation Admission studies Imaging studies

Serologic studies

Etiologic evaluation

CXR Non-contrast Head CT (in stage 3-4 encephalopathy) CT abdomen with liver volume or MRI abdomen with liver volume. If a CT or MRI cannot be done safely and in a timely manner, then bedside abdominal sonogram with Doppler should be ordered to assess for portal vein patency ECG TTE Liver function panel PT/INR Complete blood count w/ differential Fibrinogen D-Dimer Acetaminophen level (adduct if available) Toxicology screen Electrolytes (sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, magnesium, phosphate, uric acid) Blood cultures Arterial Blood Gas Arterial lactate Type and screen Pregnancy test Arterial Ammonia Amylase Lipase HIV 1,2

Serial studies CXR Non-contrast HCT if patient received intracranial monitor or if intracranial hemorrhage present (repeat HCT every 6 h until hemorrhage size stable) Note that HCT may be normal in the context of elevated intracranial pressure.

Cytomegalovirus IgG Epstein Barr virus IgG Hepatitis A virus IgM Hepatitis B virus-DNA (quant) Hepatitis B surface antigen Hepatitis B surface antibody Hepatitis B core antibody Hepatitis C antibody Hepatitis C virus-RNA (quantitative) Hepatitis E antibody Alpha-fetoprotein Ceruloplasmin Serum protein electrophoresis Alpha smooth muscle antibody Antimitochondrial antibody Anti-nuclear antibody Liver kidney microsome antibody HSV1 IgM VZV IgM

Arterial blood gas Arterial lactate Glucose q6h ABO (two separate tests, 2 h apart) Repeat PT/INR q6h Repeat transaminase level q6h Repeat total and direct bilirubin q6h Serum Na, K, Mg, PO4 q6h Serum Osmolarity or Osmolality gap (if using Mannitol) Repeat fibrinogen and D-Dimer if patient received PCC or rFVIIa or in the context of DIC

CXR chest x-ray, DIC disseminated intravascular coagulopathy, HCT head CT, MRI magnetic resonance imaging, PCC prothrombin complex concentrates, Q6h every 6 h, rFVIIa recombinant factor VIIa, TTE transthoracic echocardiogram.

eases (AASLD) [16•] can be found in Table 4. & In general, for all HE patients there are five major goals of treatment: (1) Stabilization;

(2) Addressing modifiable precipitating factors; (3) Lowering blood ammonia; (4) Managing elevated intracranial pressure, if present; and (5) Managing complications of liver failure that can contribute to encephalopathy, namely hyponatremia. & Stabilization Patients with chronic/subacute liver failure and mild HE may be managed in the outpatient setting. Patients with grade I or II hepatic encephalopathy in the context of chronic liver failure can typically be managed on a hospital floor or step-down unit. Frequent neurologic examinations should be per-

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Table 4. Etiology of acute liver failure in United States Etiology

Frequency

Acetaminophen overdose Other including: Hypoxic injury Neoplastic infiltration Budd-Chiari Heat-stroke Mushroom ingestion Wilson’s disease Acute fatty liver of pregnancy Unknown Other drugs including: PrescriptionTrimethoprim-sulfamethoxazole, rifampin-isoniazid, amoxicillin-clavulanate, Isoniazid, Sulfasalazine, pyrazinamide, dapsone, itraconazole, ketoconazole, ciprofloxacin, doxycycline, nitrofurantoin, didanosine, efavirenz, abacavir, disulfiram, phenytoin, valproic acid, carbamazepine, amiodarone, statins, gemtuzumab, propythiouracil, etodolac, diclofenac, isoflurane, halothane, nicotinic acid, imipramine, terbinafine, methyldopa, labetalol, tolcapone, allopurinol IllicitsMDMA (Ecstasy), cocaine HerbalHerbalife, hydroxycute, kava kava, comfrey, senecio, greater celandine, He shon we, lipokinetix, ma huang Hepatitis B Hepatitis A

39 % 19 %

18 % 13 %

7% 4%

formed to monitor for deterioration. Patients with rapidly progressing HE, acute liver failure, and patients with grade III or IV encephalopathy should be managed in an ICU and often require intubation and hemodynamic support. Because liver failure patients may have a low systemic vascular resistance and volume depletion, initial fluid resuscitation is often required. In the context of low serum albumin levels, pulmonary edema can be a risk with aggressive volume administration. In addition, concomitant renal insufficiency that may accompany acute liver failure in more than 50 % of patients, can lead to volume overload. Careful monitoring of oxygenation is therefore required [20]. A reasonable blood pressure goal is a mean arterial pressure ≥65 mm Hg, or if an ICP monitor is in place, a cerebral perfusion pressure ≥60 mm Hg. & Addressing modifiable and etiology specific precipitating factors Drug overdose is the leading cause of liver failure in the United States (Table 5). Liver failure because of acetaminophen toxicity is typically associated with single ingestion in excess of 10 g, and unlikely with less than 4 g [21]. However, in the setting of alcohol abuse, malnutrition, coingestion, chronic ingestion, or polypharmacy, a far lower intermittent dosage may result in hepatocellular loss [22]. Attempts should be made to identify all illicit drug use, nonprescription therapy, alternative/nontraditional and herbal remedy use, and to inquire about nonmedicinal ingestions (eg, am-


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Table 5. American Association for the Study of Liver Diseases (AASLD) Guidelines for the Management of Acute Liver Failure 2011 [16•] Recommendation Diagnosis and initial evaluation Patients with acute liver failure should be hospitalized and monitored frequently, preferably in an ICU setting Transfer to a transplant center should be initiated early in the evaluation process of acute liver failure The etiology of acute liver failure should be investigated to guide management Etiology-based therapy Acetaminophen poisoning: Activated charcoal should be administered in patients with known or suspected acetaminophen overdose within 4 h of ingestion, prior to starting N-acetylcysteine (NAC) Acetaminophen poisoning: Begin NAC immediately in patients who have ingested quantities of acetaminophen to indicate impeding or evolving liver failure or who have serum drug levels or rising aminotransferases that would suggest impending or evolving liver injury. Acetaminophen poisoning: NAC may be useful in cases of acute liver failure with possible acetaminophen ingestion or when there is no confirmed ingestion but aminotransferases suggest acetaminophen poisoning Mushroom poisoning: In acute liver failure patients with suspected or known mushroom poisoning (usually Amanita phalloides), penicillin G and NAC administration can be considered Mushroom poisoning: Patients with acute liver failure because of mushroom poisoning should be listed for transplant because this may be the only lifesaving treatment Drug induced liver injury (DILI): Caregivers should obtain the details of ingestion, amount, and timing of last dose of all prescription and nonprescription drugs, herbs and dietary supplements in the last year. Drug induced liver injury (DILI): Caregivers should determine the ingredients of nonprescription medications when possible Drug induced liver injury (DILI): Discontinue all but essential medications if drug induced hepatotoxicity is suspected Drug induced liver injury (DILI): NAC may be beneficial Viral hepatitis: There is no specific treatment for hepatitis A or E and supportive care is recommended Viral hepatitis: Nucleoside (lamivudine) and nucleotide analogs should be considered for hepatitis B related acute liver failure and for the prevention of post-transplant recurrence. Viral hepatitis: Patients with acute liver failure because of herpes virus or varicella zoster virus should be treated with acyclovir (5 10 mg/kg q8h for at least 7 days) and should be considered for transplant. Wilson disease: To diagnose or exclude Wilson disease the following work-up should be obtained- ceruloplasmin, serum and urinary copper levels, slit-lamp examination for Kayser-Fleisher rings, hepatic copper levels by biopsy (when feasible), total bilirubin/alkaline phosphatase ratio Wilson disease: If Wilson disease is the likely cause of acute liver failure, prompt consideration should be given to transplant Autoimmune hepatitis: If autoantibodies are negative and autoimmune hepatitis is the suspected cause of acute liver failure, liver biopsy is recommended Autoimmune hepatitis: Prednisone 40 60 mg/d may be considered for patients with coagulopathy, mild hepatic encephalopathy and autoimmune hepatitis Autoimmune hepatitis: Patients should be considered for transplant even when steroids are being administered Acute fatty liver of pregnancy or HELLP syndrome: Delivery of the infant is recommended.

Grade of evidence III III III I

II

III

III III III

III III I III III III

III

III III III III III

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Table 5. (Continued) Recommendation Transplant may be considered if hepatic failure does not resolve quickly following delivery Acute ischemic injury: Cardiovascular support is the treatment of choice Budd-Chiari syndrome: Hepatic vein thrombosis with acute liver failure is an indication for transplant as long as underlying malignancy has been excluded. Malignant infiltration: In patients with a history of cancer, or massive hepatomegaly, malignancy should be suspected as a cause of acute liver failure and imaging and liver biopsy should be obtained. Indeterminate Etiology: Liver biopsy may be appropriate to identify an etiology and guide treatment, if the initial workup is inconclusive Management of encephalopathy and elevated intracranial pressure Lactulose may be used orally or rectally in the early stages of encephalopathy, but should not be used to the point of diarrhea and may lead to bowel distention which can obscure the surgical field during liver transplant Patients with grade III or IV encephalopathy should be intubated Seizures should be treated with benzodiazepines and phenytoin. Prophylactic phenytoin is not recommended. Intracranial pressure monitoring is recommended in patients with acute liver failure with high grade encephalopathy who are awaiting and undergoing liver transplant Frequent (hourly) neurologic evaluation is recommended to identify clinical evidence of intracranial hypertension and/or neurologic deterioration When ICP is elevated a mannitol bolus (0.5 1.0 g/kg body weight) is recommended as first line therapy, however, prophylactic administration of mannitol is not recommended. In patients with acute liver failure at a high risk of cerebral edema (grade III or IV encephalopathy, ammonia 9150 μM, acute renal failure, hypotension requiring vasopressors), the use of prophylactic hypertonic saline to raise sodium to 145 155 meq/L is recommended. For intracranial hypertension refractory to osmotic agents, short acting barbiturates and mild therapeutic hypothermia (34 °C 35 °C) may be considered as a bridge to liver transplant. Steroids should not be used to treat elevated ICP in patients with acute liver failure. Infection Periodic surveillance cultures to detect bacterial and fungal infections are recommended. Antibiotic treatment should be initiated promptly according to culture results as soon as active infection or deterioration are detected. Prophylactic antibiotics and antifungals have not been shown to improve outcomes in acute liver failure and are not recommended. Coagulopathy Transfusion and/or replacement therapy for thrombocytopenia or prolonged PT/INR is recommended only in the context of hemorrhage or prior to invasive procedures. Prophylaxis Patients with acute liver failure in the ICU should receive gastric ulcer prophylaxis with H2 blockers or proton pump inhibitors Renal failure and hemodynamics Fluid resuscitation to maintain adequate intravascular volume is recommended. The initial treatment of hypotension should be with intravenous normal saline. If renal replacement therapy is required for acute renal failure, continuous dialysis is recommended rather than intermittent dialysis. Pulmonary artery catheterization is associated with significant morbidity and is rarely necessary in patients with acute liver failure. A volume challenge can be used to ensure appropriate volume status.

Grade of evidence III II III

III

III

III III III III II-2 I

II-3 I III

III

III

I

III I III


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Table 5. (Continued) Recommendation

Grade of evidence

Vasopressors such as norepinephrine should be used in volume-refractory hypotension or to augment cerebral perfusion pressure. Vasopressin and terlipressin can be added to norepinephrine, but should be used cautiously in patients with severe encephalopathy and elevated ICP. Goals of circulatory support in acute liver failure should be MAP ≥75 mm Hg and CPP 60 80 mm Hg Metabolic management Nutritional status, glucose, phosphate, potassium and magnesium levels should be monitored frequently and corrected as necessary. Prognostication Current prognostic models do not adequately predict outcome or determine candidacy for transplant. Reliance solely upon prognostic models is not recommended. Transplant Urgent liver transplant is indicated for acute liver failure where prognostic indicators signal a high likelihood of death. Use of living donor or auxiliary liver transplant remains controversial, but may be considered in the setting of limited organ supply. Liver support systems are not recommended outside of clinical trials.

II-1

II III

III

II-3 II-3 II-1

MAP mean arterial pressure.

anita mushroom, nutritional, or fitness supplements) that are new or noteworthy [23]. In some countries (notably Bangladesh, Russia, Pakistan, Mexico, and India), hepatitis E is a major cause of acute liver failure and tends to

Table 6. Factors that precipitate hepatic encephalopathy in chronic liver failure Factor

Example

Increased ammonia production or absorption

Gastrointestinal bleeding Infection Excess dietary protein Electrolyte disarray (hypokalemia) Constipation Metabolic alkalosis Alcohol Narcotics Benzodiazepines Diarrhea Vomiting Diuretics Hemorrhage Large volume paracentesis Spontaneous shunts Therapeutically placed shunts Portal vein thrombosis Hepatic vein thrombosis Hepatocellular carcinoma

Drugs

Volume depletion

Porto-systemic shunting Vascular occlusion Other

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Curr Treat Options Neurol (2014) 16:297 cause more severe disease in pregnant women [16•, 20]. In patients with chronic liver failure precipitating factors that can increase ammonia production or reduce clearance should be investigated (Table 6). Modifiable precipitants such as gastrointestinal bleeding, dehydration, infection, electrolyte disturbance, and portal or hepatic vein thrombosis may constitute medical emergencies and should be addressed immediately.

&

Lowering blood ammonia

Elevated serum ammonia levels are detected in up to 80 % of patients with hepatic encephalopathy. Ammonia is produced from glutamine by enterocytes, as well as generated by colonic bacteria through the catabolism of nitrogenous sources including dietary proteins and secreted urea. Under normal conditions, ammonia is transported via the portal vein to the liver and converted back to glutamine. In the context of liver failure or portal-systemic shunts, serum ammonia levels become elevated. Furthermore, since 20 % of the bodies ammonia is excreted renally, concomitant renal failure can lead to further hyperammonemia. In addition, it is important to recognize that hypokalemia increases renal ammonia production and should be corrected expeditiously. Alkalosis can exacerbate ammonia entry into the brain by limiting conversion to NH4+, a charged particle that cannot cross the blood brain barrier. In contrast to subacute or chronic liver failure, hyperammonemia can develop rapidly in acute liver failure, outstripping osmotic compensatory mechanisms with consequent cerebral edema and elevated ICP. Blood ammonia levels are linked to the development of HE and may predict ICP. Brain microdialysis studies have found that arterial ammonia levels correlate with brain glutamine levels and that both are associated with ICP [24]. Arterial ammonia levels G75 μmol are rarely associated with elevated ICP, whereas sustained levels 9150 200 μmol are strongly associated [25, 26]. Ammonia lowering agents may act by decreasing ammoniagenic substrates (eg, lactulose enema, restriction of dietary protein), inhibiting ammonia production (eg, antibiotics, lactulose, lactitol, modification of colonic flora with lactobacillus) or by ammonia removal (eg, ornithine-aspartate, benzoate). Oral ammonia lowering agents such as lactulose, lactitol, and rifaxamin, which are commonly used for HE in the context of subacute/chronic liver failure, are controversial in acute liver failure patients, particularly those who are candidates for transplant. Lactulose can obscure the operating field during orthotopic liver transplant, and in rare cases, can lead to megacolon and bowel ischemia [27]. Because acute renal failure is not uncommon in the context of acute liver failure, neomycin (and other nephrotoxic drugs) should not be used in this situation [17, 28]. In patients with chronic liver failure, lactulose ± rifaximin can be used for acute encephalopathy exacerbations or as chronic prophylactic therapy for patients with recurrent encephalopathy. A recent randomized trial of patients with chronic liver disease has shown significantly improved complete HE reversal rates and reduced mortality using the combination of rifaxamin plus lactulose compared with lactulose alone [29•].

&

Managing elevated ICP

Cerebral edema occurs in nearly 80 % of patients with acute hepatic failure and is the leading cause of death [19, 30]. The risk of cerebral edema correlates with the clinical grade of encephalopathy such that 25 % 35 % of


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grade III and 65 % 75 % of grade IV patients have cerebral edema [31]. Among grade III/IV encephalopathy patients, 86 % 95 % will have elevated ICP, primarily related to cerebral edema [32]. In one study of acute liver failure patients, 82 episodes of elevated ICP (with a median value of 33 mm Hg for a median duration of 60 min) occurred in 21 patients (95 % of patients) who were monitored for a median of 6 days [32]. This study suggests that ICP elevations were both severe and frequent and may require evaluation and medical management. There is some evidence that protocolized ICP management can improve neurologic outcomes [32]. Figure 1 details a flow diagram for management of elevated ICP in patients with acute liver failure. Specific strategies for managing elevated ICP are discussed below. In general, the head of the bed should be elevated for all patients to promote cerebral venous drainage. Adequate management of pain, agitation, hyponatremia, fever, and shivering is also critical. Grade III/IV patients should receive osmotic therapy to target a sodium of 150 155 meq/L using hypertonic saline or adjustment of the dialysis bath. Boluses of mannitol or 23.4 % saline can be used for clinical deterioration, radiographic evidence of herniation or spikes in ICP values. Hyperventilation, hypothermia, and pentobarbital are reserved for patients with refractory elevations in ICP. It is important to note that patients may have elevations in ICP with normal head CT findings [18, 19, 64]. Because seizures can elevate ICP, patients should be carefully monitored and treated appropriately. The true incidence of seizure in fulminant liver failure patients is not clear. Hypoglycemia, hyponatremia, uremia, and intracranial hemorrhage, which are all comorbidities of liver failure, are common causes of seizure. Typically, liver failure induces a GABAnergic state, with concomitant low NMDA activity, which is generally protective against seizures. Conversely, the post-transplantation state is accompanied by acute GABAnergic withdrawal and is a higher risk time for seizure activity. In a study conducted in 42 patients with acute liver failure, seizure activity was identified in up to 32 % of patients [33]. The authors do not provide any imaging, medication, or metabolic data to determine if other etiologies for seizure were present. In addition, some patients included in this study were post-transplant. Another study found a seizure rate of 25 % in acute liver failure patients but similarly did not account for confounders and did not use continuous EEG monitoring [34]. Continuous EEG monitoring is recommended in all HE grade III/IV patients, patients with intracranial hemorrhage, or patients with clinical seizure episodes. Since non-convulsive seizures occur in 10 % 20 % of critically ill patients [35–37], full montage continuous EEG monitoring is the best form of detection. There are mixed data on the utility of phenytoin prophylaxis in acute liver failure patients [33, 34]. Patients who have had seizures should receive antiepileptic treatment. Prophylaxis can be considered for those who have intracranial hemorrhage or very severe cerebral edema, in whom a seizure might result in herniation because of elevated intracranial pressure. & Managing hyponatremia Encephalopathy because of hyponatremia depends on the rate of development of hyponatremia and the absolute sodium level. Rapidly developing hyponatremia (G12 24 h) and serum sodium G120 meq/L is more likely to result in symptoms of confusion, seizure (generalized tonic clonic),

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Figure 1. Schematic for management of elevated intracranial pressure. (Reprinted from Frontera and Kalb [127]. With kind permission from Springer Science + Business Media.)


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muscle cramps, generalized weakness, and in severe cases, coma. Chronic hyponatremia, that persists for 924 48 h is associated with the generation of idiogenic osmoles that are toxic to brain myelin. Rapid correction of chronic hyponatremia can result in central pontine and/or extra-pontine myelinolysis (osmotic demyelination) characterized by headache, lethargy, coma, seizures, and focal deficits. MRI in these cases may demonstrate white matter changes on T2 or FLAIR sequences, typically in the pons and brainstem. Therefore, judicious and measured correction to avoid such complications is required in patients with chronic hyponatremia. Treatment for symptomatic patients who develop acute hyponatremia (G24 h) consists of rapid correction of sodium at a rate of 1.5 2 meq/L per hour until symptoms resolve (usually to a sodium of about 120 meq/L). Patients with chronic hyponatremia (924 48 h) are at greatest risk for osmotic demyelination if the sodium is corrected 920 meq/L per day and/or if the baseline sodium is G105 meq/L. Chronic hyponatremia patients should be corrected by no more than 8 12 meq/L per day or 18 meq/L in 48 h. Options for treatment of hyponatremia in chronic liver failure patients include free water restriction, hypertonic saline, increased oral sodium intake in the form of salt tablets, or high sodium food, and V2 (vasopressin) receptor antagonists, which produce a pure aquapheresis.

&

Treatments to avoid

Because of the high risk of concomitant renal failure with acute liver failure (ALF), nephrotoxic drugs and contrast agents should be avoided. Other therapies that have not shown benefit in acute liver failure include charcoal hemoperfusion [38], insulin and glucagon [39], systemic corticosteroids [40–42], L-ornithine Laspartate (LOLA) [43], and prostaglandin E. [44]. LOLA may have some benefit in patients with hepatic encephalopathy related to chronic liver failure (see below).

Diet and lifestyle & &

&

& &

Nitrogen balance (related to protein intake) is intimately related to the development of HE in patients with underlying cirrhosis. A randomized trial of a low protein compared with a normal protein diet in cirrhotics revealed that HE did not differ significantly between groups. The low protein group showed higher rates of protein breakdown [45]. A cohort study of patients with alcoholic hepatitis demonstrated that low protein intake was associated with worsened HE [46]. Therefore, a diet with a normal content of protein is recommended. The daily diet should consist of 35 40 kcal/kg/day and 1.2 1.5 g/kg/day of protein (Level 1A recommendation from the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus) [47••]. Obese patients may require fewer daily calories. Diets containing 35 45 g of daily fiber are encouraged (Level 2B recommendation from the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus) [47••]. Small meals throughout the day and a late-night snack of complex carbohydrates are encouraged to minimize protein catabolism (Level 1A recommendation from the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus) [47••].

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&

&

&

&

&

& &

Nitrogen balance and psychometric testing in HE patients have been shown to improve with a vegetable protein, rather than animal protein diet [48]. A diet rich in vegetable and dairy protein is recommended (Level 2B recommendation from the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus) [47••]. Nutritional supplements (such as amino acids, multivitamins, lipids, or branched chain amino acids) have not been shown to improve mortality or ascites but have been shown to improve HE in a meta-analysis of seven randomized controlled trials with 262 patients with alcoholic hepatitis [49]. Clinically apparent vitamin deficiencies should be treated and a 2-week course of multivitamins is reasonable in patients with decompensated cirrhosis or those at risk of malnutrition (Level 2A recommendation from the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus) [47••]. Increased levels of aromatic amino acid precursors to monoamine neurotransmitters may contribute to encephalopathy in the context of liver failure. Modification of the dietary ratio of branched chain amino acids to aromatic amino acids may improve HE, particularly in patients who are intolerant of dietary protein (Level 2B recommendation from the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus) [47••, 50]. However, a systematic review of 11 randomized trials with 556 patients failed to demonstrate substantial benefit [51]. Hyponatremia should be corrected slowly. (Level 1A recommendation from the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus) [47••]. Rapid sodium correction (98 12 meq/ day) in patients with chronic hyponatremia can be complicated by central myelinolysis syndrome. Long-term manganese supplementation should be avoided (Level 2B recommendation from the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus) [47••]. All patients with cirrhosis should undergo regular nutritional assessments (Level 1A recommendation from the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus) [47••].

Pharmacologic treatment Acetaminophen poisoning N-acetylcysteine N-acetylcysteine (NAC) has been demonstrated to reduce hepatotoxicity, and improve mortality and cerebral function after acetaminophen overdose [52– 56]. NAC primarily acts to replenish glutathione stores. Glutathione conjugation is the mechanism by which the harmful acetaminophen metabolite Nacetyl P-benzoquinoneimine (NAPQI) is normally detoxified. NAC may have additional antioxidant and vasoactive benefits and has been shown to improve liver blood flow in patients with septic shock [57]. The use of NAC to reverse acetaminophen poisoning is generally guided by the Rumack-Matthew nomogram (Fig. 2), which plots the time from ingestion against the


Page 15 of 37, 297

Figure 2. Rumack-Matthew nomogram for N-acetyl cysteine administration in the context of acute acetaminophen poisoning. (Reproduced with permission from Rumack and Matthew [58]. Copyright 1975 by the AAP.)

Standard dosage

serum acetaminophen concentration [58]. Serum acetaminophen concentrations should be drawn ≥4 h from ingestion to ensure that peak serum concentrations are measured. Other indications for NAC include ingestion of a single dose of acetaminophen 9150 mg/kg or ≥7.5 g and a acetaminophen level is not available within 8 h, acetaminophen level 910 mcg/mL and an unknown time of ingestion, acetaminophen ingestion, and any evidence of liver injury. Optimally, NAC should be started prior to liver injury (as indicated by elevated ALT) or within 8 h of ingestion. NAC should also be strongly considered for patients with early stage nonacetaminophen induced acute liver failure because NAC has a generally favorable safety profile, and there is mounting evidence suggesting that NAC administration is associated with improved transplant-free survival among other etiologies of acute liver failure [59]. Treatment should be begin immediately with a loading dose of 150 mg/kg in 500 mL dextrose 5 % IV over 60 min, followed by maintenance dose 50 mg/ kg IV over 4 h (12.5 mg/kg/h), then 100 mg/kg in 1000 mL dextrose 5 % IV over 16 h (6.25 mg/kg/h). An oral NAC regimen is a reasonable alternative and consists of a loading dose of 140 mg/kg PO, followed by 70 mg/kg PO q 4 h for a total of 17 doses.

297, Page 16 of 37

Curr Treat Options Neurol (2014) 16:297 Contraindications

Main drug interactions

An intravenous regimen is preferred in patients who are obtunded, vomiting, and have acute liver failure or have bowel obstruction or ileus. None.

Main side effects

Hypersensitivity (non-IgE mediated anaphylaxis) can occur in10% 20 % of patients with intravenous administration. In those who develop urticaria, angioedema, or wheezing, the infusion should be stopped and corticosteroids, antihistamines, and intramuscular epinephrine should be administered. The infusion can be resumed once symptoms resolved or oral NAC can be used. In patients who develop hypotension, respiratory failure, or systemic anaphylaxis, the infusion should be stopped and oral NAC can be used as an alternative, with a much reduced risk of persistent anaphylaxis. Vomiting is common in up to 33 % of patients with oral administration. If vomiting occurs within 1 h of NAC administration, this dose should be repeated.

Special points

Treatment should continue until the acetaminophen concentration is undetectable or the serum ALT is normal or G50 % of its peak measurement and the INR G1.5 2.0

Cost/cost effectiveness

Inexpensive.

Activated charcoal

Standard dosage Contraindications Main drug interactions Main side effects Special points


Activated charcoal has been shown to reduce the incidence of liver injury after acetaminophen poisoning and is recommended within 4 h of ingestion of a single dose of acetaminophen (97.5 g) or suspected acetaminophen overdose [60]. A randomized trial has demonstrated lower serum acetaminophen levels with activated charcoal compared with gastric lavage or emesis induction [61]. If more than 4 h have passed since ingestion, activated charcoal is generally not recommended, though some studies have suggested a benefit in later administration [62]. 1 g/kg, maximum 60 g PO or by nasal or oral gastric tube. None. Activated charcoal may reduce levels of leflunomide and teriflunomide Abdominal distention, constipation, vomiting, bowel obstruction, appendicitis, aspiration. In patients who have an oral or nasal gastric tube, the activated charcoal can be diluted with sterile water to avoid tube obstruction. Gastric lavage and forced emesis are not recommended in acetaminophen poisoning. Inexpensive.

Elevated intracranial pressure Hypertonic saline Osmotic therapy draws water out of the brain parenchyma into the intravascular space along an osmotic gradient. Both mannitol and hypertonic saline have the additional rheologic benefits of lowering blood viscosity and decreasing the rigidity and volume of red blood cells.


Page 17 of 37, 297

Standard dosage

For ICP management: Loading dose 30 mL of 23.4 % saline pushed over 10 20 min via a central line, maintenance dose of 3 % saline 1 mg/kg/h titrated to a serum Na of 150 155 mEq/h. Serum Na should be checked every 6 h. For hyponatremia management: 2 % or 3 % saline at 30 50 cc/h may be reasonable depending on the baseline sodium and if the patient is acutely symptomatic. Correction at a rate of 8 12 meq/L/d is advised.

Contraindications

Hypertonic saline is relatively contraindicated in patients with chronic hyponatremia (924 48 h) because of the risk of central pontine myelinolysis with rapid sodium correction (as above). Pulmonary edema with concomitant hypoxia is also a contraindication to hypertonic saline.


None.

Main side effects

Administration of hypertonic saline is associated with pulmonary edema and can cause hypotension if pushed too rapidly. Extravasation of 23.4 % or 3 % saline from a peripheral IV can cause tissue necrosis. For this reason, these concentrations should be administered only through a central line. Lower concentrations, such as 2 % saline, can be given via a peripheral line. Hypertonic saline can be associated with renal insufficiency (less common than with mannitol). A single case report of central pontine myelinolysis has been reported when hypertonic saline was used in the context of chronic hyponatremia

Special points

Prophylactic induction of hypernatremia in patients with acute liver failure and high grade encephalopathy has been shown to reduce the incidence and severity of elevated ICP and is recommended by the American Association for the study of liver disease [16•, 63]. Hypertonic saline bolusing has been shown to reduce ICP faster than mannitol and is effective even in patients who are refractory to mannitol. Both mannitol and hypertonic saline can cause rebound cerebral edema during tapering. Both drugs should be slowly and cautiously tapered to avoid this devastating consequence. Three percent saline can be weaned to 2 % and then to normal saline.

Cost/cost effectiveness Standard dosage

Inexpensive. Mannitol 20 %: Loading dose of 1 g/kg (or 100 g if weight unknown), followed by a maintenance dose of 0.5 g/kg every 4 6 h titrated to a serum osmolarity of 300 320 mOsm or an osmolal gap (measured Osm – calculated Osm) of 50 mOsm/kg. Serum osmolarity should be checked every 6 h. The half-life of mannitol is 0.16 h. Efficacy is seen in 15 30 min, and the duration of effect is 90 min to 6 h. Mannitol has an osmotic reflection coefficient of 0.9, whereas hypertonic saline has a reflection coefficient of 1.0. Thus, mannitol is slightly more likely to cross the blood-brain barrier and leading to a degradation of the osmotic gradient and tachyphylaxis. Though AASLD guidelines recommend bolus mannitol as the first line treatment of elevated ICP in liver failure patients [16•], it may not be a practical choice in the context of relative hypotension or concomitant renal insufficiency. In patients who can tolerate additional volume and who have central line access, 23.4 % saline may be a preferable choice for acute osmotic therapy.

Contraindications

Renal insufficiency. Mannitol also causes diuresis and may be contraindicated in hypotensive and/or volume depleted patients. In patients with anuria/oliguria, mannitol can lead to volume overload. Hypersensitivity to mannitol is also a contraindication.


Mannitol may enhance the effect of hypertensive agents because of its diuresis effect. Mannitol may also augment the effect of other diuretics.

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Curr Treat Options Neurol (2014) 16:297 Main side effects

Renal insufficiency (likely because of ATN), which is reversible and more often seen if 9200 g are used daily, if serum osmolality exceeds 320 mOsm/L or if the osmolal gap is 960–75 mOsm/kg. Volume overload can occur during bolus infusion prior to the onset of diuresis. Diuresis can lead to hypotension.

Special points

Mannitol can be administered via a peripheral IV and boluses can be pressure bagged and run wide open.


Inexpensive. Pentobarbital 5 20 mg/kg bolus followed by 1 4 mg/kg/h titrated to burst suppression on EEG can be used in patients refractory to other ICP treatments. Barbiturates reduce metabolic demand and consequently cerebral blood flow, cerebral blood volume, and ICP if metabolic coupling is intact.

Contraindications

Hypersensitivity to pentobarbital.


Pentobarbital is a CYP3A4 P450 inducer and may increase the metabolism and, hence, reduce the concentrations of other drugs that are metabolized by this pathway.

Main side effects

Major risks include hypotension, inability to examine the patient because of the sedative effects of barbiturates, cardiosuppression, and immunosuppression. Other side effects include hepatoxicity, angioedema, exfoliative dermatitis, constipation, nausea, vomiting, megaloblastic anemia, and laryngospasm.

Special points

Pentobarbital has a half-life of 15 50 h. Given its long duration of effect and obscuration of the neurologic examination, its use should be limited. It should be noted that patients that achieve burst suppression on pentobarbital may have an examination that appears consistent with brain death: no cranial nerve reflexes, fixed pupils, no response to stimulation, and no respiratory drive. A brain death examination cannot be performed unless an adequate time has been allowed for pentobarbital to be metabolized.


Moderately expensive.

Hyponatremia management Conivaptan

Standard dosage Contraindications Main drug interactions Main side effects

Conivaptan (intravenous mixed V2 and V1a receptor antagonist) is FDA approved for the treatment of euvolemic hyponatremia and SIADH. Conivaptan was studied in a randomized, placebo-controlled trial of 84 patients with euvolemic or hypervolemic hyponatremia with a baseline sodium of 115 130 meq/L. After 4 days of treatment, compared with placebo, conivapatan significantly raised sodium by 6.3 meq/L using 40 mg/d dose and 9.4 meq/L using 80 mg/d dose [65]. Loading dose: 20 mg IV over 30 min followed by 20 40 mg over 24 h (0.83 mg/h) for 2 4 days. Hypersensitivity to conivaptan or corn/corn products, hypovolemia, concurrent use with strong CYP3A4 inhibitors, anuria. Conivaptan is metabolized via CYP3A4 and may interact with other drugs that are metabolized via this pathway. There are some concerns that the V1a antagonism of conivaptan may cause hypotension, increased risk of variceal bleeding, or renal dysfunction. Other common reactions include hypokalemia, injection site pain, and fever.

Curr Treat Options Neurol (2014) 16:297 Special points


Page 19 of 37, 297 Vaptan drugs are attractive in liver failure patients with volume overload and hyponatremia because they can provide diuresis (pure aquapheresis) while simultaneously raising serum sodium values. However, in patients with ICP crisis, these drugs may not provide a rapid enough rise in sodium to have an impact on ICP in a meaningful time frame. Conivaptan is typically used over 3 days. After this time frame, alternative means of maintaining a normal serum sodium must be sought. There is no oral version of conivaptan, and many hospitals restrict its use to the ICU setting, substantially limiting its long-term utility. Vaptan use is ineffective in anuric patients. Expensive and restricted in many hospitals.

Tolvaptan

Standard dosage Contraindications

Tolvaptan is not recommended in patients with liver disease (see below). Tolvaptan (oral selective V2 receptor antagonist) is FDA approved for the management of euvolemic hyponatremia, SIADH, and hyponatremia-associated with heart failure and cirrhosis. Tolvaptan has been studied in the SALT1 and SALT2 randomized trials of 448 patients with SIADH, euvolemic hyponatremia, cirrhosis, or heart failure. Compared with placebo, tolvaptan leads to a significant increase in serum sodium after 4 days of treatment (135 meq/L vs 130 meq/L) and after 30 days of treatment (136 meq/L vs 131 meq/L) [66]. 15 mg PO qd, may increase to 30 60 mg PO qd titrating at 24-h intervals. Hypovolemia, concurrent use with strong CYP3A4 inhibitors, and anuria.


Tolvaptan is metabolized via CYP3A4 and may interact with other drugs that are metabolized via this pathway.

Main side effects

The US FDA issued a safety warning in April 2013 for tolvaptan because of the side effects of progression of kidney disease in those with polycystic kidney disease and elevated liver enzymes. Tolvaptan should generally not be used in patients with liver disease including cirrhosis and should not be used for more than 30 days. Fluid restriction should be avoided during the first 24 h of use. Other common reactions include fever, hyperglycemia, hypernatremia, GI bleeding, constipation, anorexia, hepatotoxicity (≤4 %), stroke, deep vein thrombosis (DVT)/pulmonary embolism (PE), diabetic ketoacidosis (DKA), disseminated intravascular coagulation (DIC), intracardiac thrombus, ischemic colitis, respiratory failure, rhabdomyolysis, urethral hemorrhage, vaginal hemorrhage, and ventricular fibrillation.

Special points

Tolvaptan is only orally available, and gut absorption may be limited in critically ill patients and in those will bowel wall edema or diarrhea. Like conivaptan, the slow rise in sodium generated by tolvaptan is ideal for patients without ICP crisis who have chronic hyponatremia and volume overload. However, tolvaptan is not ideal for patients with ICP crisis in whom rapid induction of hypernatremia is desired.


Expensive, limited availability, and restricted in many hospitals.

Hepatic encephalopathy management in chronic liver disease Standard dosage

20 30 g (30 45 mL) PO 3-4 times per day, dose may be titrated every 1 2 days to produce 2-3 soft stools per day. In patients with acute hepatic encephalopathy 20 30 g (30 45 mL) PO every h until a bowel movement

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Curr Treat Options Neurol (2014) 16:297 occurs followed by gradual reduction. An alternative to oral administration is a retention enema (200 g diluted with 700 mL water or NS via rectal balloon catheter, retain for 30 60 min and repeat every 4 6 h as needed). Contraindications

Main drug interactions Main side effects

Special points

Cost/cost effectiveness Standard dosage Contraindications Main drug interactions

Do not use in patients requiring a low galactose diet. None. Adverse reactions include dehydration related to diarrhea, hypernatremia (related to dehydration), hypokalemia, abdominal distention, cramping, nausea, and vomiting. Lactulose metabolism in the gut leads to lower colonic pH and conversion of NH3 to NH4+, which is nonabsorbable. Lactulose additionally causes catharsis and less time for ammonia resorption as well as replacement of colonic flora with nonurease producing lactobacillus. Lactulose has been shown to improve hepatic encephalopathy in placebo controlled randomized trials in 70 % 80 % of patients [29•, 67–70]. Lactulose should be administered in suspected hepatic encephalopathy even if the serum ammonia is not dramatically elevated. It may be used for short-term exacerbations of HE or as a chronic treatment/prophylaxis regimen. Inexpensive. 550 mg PO BID or 400 mg q 8 h for 5 10 days. Hypersensitivity to rifaximin. Rifaxamin may diminish the effect of sodium picosulfate.

Main side effects

More common adverse reactions (occurring in 910 % of patients) include peripheral edema, ascites, nausea, dizziness, and fatigue. Less common reactions include chest pain, headache, depression, fever, amnesia, confusion, hypoesthesia, pain, vertigo, tremor, muscle spasms, arthralgia, myalgia, pruritus, rash, cellulitis, hypo/hyperglycemia, hyperkalemia, hyponatremia, abdominal pain, anorexia, dehydration, esophageal varices, weight gain, xerostomia, anemia, flu-like symptoms, pharyngitis, rhinitis, epistaxis, dyspnea, pneumonia, and upper respiratory infection.

Special points

Rifaximin is typically added in patients who have an inadequate response to lactulose or who cannot tolerate lactulose, though a recent randomized trial in patients with chronic liver failure has suggested improved rates of complete HE reversal and reduced mortality with the combination of lactulose and rifaximin compared with lactulose alone [29•]. Randomized trials have also established the efficacy of rifaximin as a prophylactic agent for HE [71], and it has been shown to be well tolerated for long-term use [72].


Moderately expensive. For acute hepatic encephalopathy exacerbation : 500 2000 mg PO q 6 8 h or 4 12 g total daily dose divided every 4 6 h for 5 days. For chronic hepatic encephalopathy, 4 g PO qd. Because neomycin is more toxic than other aminoglycosides, it should not be administered intravenously.

Contraindications Main drug interactions

Hypersensitivity to neomycin or aminoglycosides, bowel obstruction, and inflammatory bowel disease. Since a major side effect of neomycin is renal toxicity, neomycin may enhance the nephrotoxic effects of other medications such as amphotericin B, 2nd 4th generation cephalosporins, cisplatin, colistimethate, cyclosporine, gallium, loop diuretics, and vancomycin. Neomycin may increase the ototoxicity of carboplatin, and loop diuretics. Neomycin may increase the


Page 21 of 37, 297 neuromuscular blockade effect of abobotulinumtoxin A, onabotulinumtoxin A, rimabotulinumtoxinB, capreomycin, colistimethate, and other neuromuscular blocking agents. Neomycin may decrease the metabolism and/or enhance the effect of vitamin K antagonists, acarbose, bisphosphonates, and tenofovir. Aminoglycosides including neomycin may decrease serum concentrations of cardiac glycosides, sorafenib, and sodium picosulfate.

Main side effects

Neomycin carries a US FDA black box warning for nephrotoxicity particularly in the context of pre-existing renal insufficiency, other nephrotoxic medications, dehydration, and older age. There is also a black box warning for neuromuscular blockade and respiratory failure particularly if neomycin is dosed soon after other neuromuscular blocking agents. There is a third black box warning for ototoxicity (both vestibular and auditory). Ototoxicity is dose dependent as well as duration dependent.

Special points

Neomycin is reserved as a second tier therapy because of its toxic side effects and lack of efficacy in randomized trials.

Cost/cost effectiveness Special points

Inexpensive. L-ornithine-L-aspartate (LOLA) enhances metabolism of ammonia to glutamine by activating key enzymes carbamyl phosphate synthetase and ornithine-carbamyl transferase. Randomized trials have shown some benefit in improving serum ammonia concentrations and mild hepatic encephalopathy [73–75], but LOLA has not been compared directly with lactulose and does not show efficacy in the context of acute liver failure [43]. Depending on the brand, 1 2 capsules per day.

Standard dosage Contraindications Main drug interactions Main side effects Special points


Hypersensitivity to the formulation. None. Bloating and flatulence. Probiotics, such as lactobacillus, favor colonic colonization with non-urease producing bacteria. A meta-analysis of seven trials with 550 participants found that probiotics lowered serum ammonia levels compared with placebo [76]. Because capsules must be opened to administer via an oral or nasogastric tube, this can lead to airborne dissemination of bacteria colonies. Therefore, lactobacillus is not typically administered through a feeding tube and is not commonly used in an ICU setting. There are no currently FDAapproved therapeutic or disease prevention indications for probiotics. Inexpensive.

Interventional procedures Specific interventional procedure ICP monitoring Whether ICP monitor guided therapy improves outcomes in acute liver failure with HE is a matter of debate. In 2007, the U. S. Acute Liver Failure Study Group recommended ICP monitoring in grade III/IV HE patients who are candidates for OLT and in some patients with advanced encephalopathy who are not OLT candidates, but who may benefit from aggressive neurologic management [17]. ICP monitoring may be partic-

297, Page 22 of 37

Standard procedure

Curr Treat Options Neurol (2014) 16:297 ularly useful intraoperatively at the time of organ transplant because abdominal incision has been associated with spikes in ICP [18]. In addition, intraoperative ICP monitoring can assist with management of blood pressure and anesthesia. However, in a 2013 prospective study of patients with acute liver failure conducted by the U.S. Acute Liver Failure Study Group, ICP monitoring did not lead to improved outcomes. In this study, 51 % of patients with ICP monitors had intracranial pressures exceeding 25 mm Hg and patients with monitors were significantly more likely to receive mannitol, hypertonic saline or therapeutic hypothermia. Mortality was higher in patients with elevated ICP (43 % vs 23 %, P= 0.05). Though patients who had ICP monitoring were more likely to undergo liver transplant (41 % vs 18 % of those not monitored, PG 0.001), 21-day mortality was similar between those who were monitored and those who were not (33 % vs 28 %, P=0.24). ICP monitoring did not change outcomes in acetaminophen-related liver failure patients but was significantly associated with increased mortality in nonacetaminophen patients. Hemorrhagic complications related to ICP monitoring occurred in 7 % of patients [77••]. Because this study was observational and not randomized, there is a substantial risk for physician bias in regards to which patients received ICP monitoring. Those too sick to be candidates for transplant may not have been monitored, and conversely, those rapidly improving may not have undergone monitoring. The BEST TRIP randomized, controlled trial of ICP monitoring in traumatic brain injury similarly did not show a benefit for ICP monitorguided therapy compared with therapy based on imaging and clinical examination [78]. In addition, in order to place an ICP monitor, coagulopathy reversal agents must be administered. Liver disease patients may have coagulation factor and fibrinogen deficiencies because of synthetic dysfunction, as well as thrombocytopenia because of splenic sequestration, disseminated intravascular coagulopathy, or platelet abnormalities because of uremia. Transfusion to correct coagulopathy can be associated with serious complications such as transfusion-related acute lung injury (TRALI), arterial and venous thrombosis, volume overload, pulmonary edema, and disseminated intravascular coagulopathy, with may mask spontaneous liver recovery. Based on these data and the relatively high risk of invasive ICP monitoring in the context of liver failure associated coagulopathy, ICP monitoring should only be considered in select circumstances. Patients with rapidly deteriorating examinations or worsening radiographic cerebral edema despite maximal osmotic therapy may be optimal candidates for ICP monitoring. ICP monitors are typically placed at the bedside. A single dose of preoperative antibiotics (cefazolin or vancomycin) is used prior to monitor placement. Local anesthesia (1 % lidocaine) is administered and an incision is made at Kocher’s point (10 cm from the glabella or 11 cm from the nasion and 2 3 cm lateral to midline). The monitor may be placed on either the left or right side of the head, though often the nondominant side is chosen. The periosteum is removed via blunt dissection and a burrhole is created using a twist drill. The dura is incised sharply and the bolt is inserted. A head CT to check bolt placement and rule out procedure related hemorrhage is performed after placement.


Page 23 of 37, 297

Contraindications

Coagulopathy can be considered adequately corrected for placement of an intracranial monitor with laboratory values as follows: INR G1.4, platelets 950,000/mm3, fibrinogen 9100 mg/dL and a normal PTT. Aggressive coagulopathy reversal prior to ICP monitor placement is critical. Recombinant factor VIIa (rFVIIa) has been recommended for coagulopathy reversal prior to ICP monitor placement [7, 26]; however, use of rFVIIa alone does not replete other depleted coagulation factors (notably II,V, IX, and X) and is associated with a higher risk of DIC than other reversal agents. Arterial thrombotic events are more common with rFVIIa than other agents and have been reported to occur in as many as 8.5 % of patients [79]. Alternatives to rFVIIa include fresh frozen plasma (FFP) and unactivated prothrombin complex concentrates (PCC), and activated prothrombin complex concentrates (aPCC, sometimes referred to as FEIBA). Most PCC moieties include varying amounts of factors II, VII, IX, X, and protein C and S. Four factor PCC containing larger amounts of factor VII than previously available versions of three-factor PCC has recently become available in the U.S. (K-centra)[80]. Because PCC does not contain factor V, additional FFP may be indicated to replace this factor in the context of liver failure (particularly if the INR is 92.0). It is important to recognize that multiple doses of rFVIIa or combining rFVIIa with PCC can dramatically increase the risk of DIC and DIC-related complications and are, therefore, not advised. An alternative to rFVIIa and PCC is FFP (dosed at 10 15 mL/kg). Limitations of FFP include a longer time to administration (because of the need for thawing), and a higher volume load, which can be problematic in liver failure patients, particularly if complicated by acute renal failure. Whether rFVIIa, PCC, or FFP is administered, all patients should receive Vitamin K 10 mg IV once [17]. In addition, cryoprecipitate is indicated if fibrinogen is G100 mg/dL. Uremia induced platelet dysfunction in the context of renal insufficiency can be corrected with DDAVP 0.3 mcg/kg once. Plasma exchange has been shown to be effective and may be an option for patients with persistent coagulopathy [81]. In patients who already have a dialysis catheter in place and who can tolerate an interruption from renal replacement therapy to undergo plasma exchange, this may be an especially attractive option.

Complications

Intracranial hemorrhage at the site of ICP monitor insertion is the most serious concern. For this reason, single lumen intracranial bolts, which require smaller caliber burrholes than other types of bolts, are recommended. Coagulopathy reversal prior to ICP monitor placement is required. Whether coagulation factors need to be corrected for the entire duration of time an ICP monitor is in place or if correction is only necessary during placement and removal of devices is a matter of debate [32]. The expense of continued aggressive correction can be considerable and medical complications such as volume overload, thrombosis, or DIC can occur with ongoing transfusions. In addition, continued coagulation correction may mask spontaneous liver recovery. Further complications stemming from procedure-related intracranial hemorrhage include elevated intracranial pressure. Management for elevated ICP can be found above and in Fig. 1.

Special points

ICP monitors are typically placed by neurosurgeons, however, trained neurointensivists may be credentialed to place such monitors at select facilities. It is important to note that patients can herniate with normal ICP values. Pressure gradients between brain compartments can cause herniation and shift, even though the absolute ICP in any given compartment is G20 mm Hg. Significant ICP gradients are present when there is 93 mm of midline shift radiographically. When basal cisterns are effaced, ICP gradients can rise quickly.

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Expensive because of the costs of transfusion to reverse coagulopathy, professional fees for monitor placement, and costs for the monitoring device itself.

Specific interventional procedure Transcranial Doppler ultrasound

Standard procedure Contraindications Complications Cost/cost effectiveness

Transcranial Doppler ultrasound (TCD) assessment of pulsatility index (peak–end diastolic flow velocity/ mean flow velocity) may be useful in patients who are not candidates for ICP monitor placement. Elevated pulsatility indices (91.5) are considered abnormal and can give a rough gauge of the likelihood of elevated ICP, though not a quantified estimate of ICP. In addition, transcranial Doppler does not provide a means of continuous ICP monitoring may have suboptimal sensitivity and specificity, according to some studies [82]. Insonation is performed with a portable Doppler machine using a 2 mHz probe at a depth of 40 70 mm. Approximately 10 % of the population do not have adequate temporal bone windows to obtain TCD waveforms. None. Moderate.

Specific interventional procedure Optic nerve sheath diameter sonography

Standard procedure

Contraindications Complications

The retrobulbar segment of the optic nerve is surrounded by meninges. The subarachnoid space surrounding the nerve sheath can expand when ICP is elevated and ultrasound measurements of optic nerve sheath diameter can therefore give an estimation of ICP. Optic nerve sheath diameter has been used to estimate ICP in pediatric acute liver failure patients [83]. A diameter 95 mm has a 88 % 96 % sensitivity, 93 % 94 % sensitivity to detect an ICP 920 mm Hg [84, 85]. Like TCD, optic nerve sheath sonography does not provide a continuous measure of ICP, but rather a stochastic estimate. The optic nerve sheath is insonated with a linear array probe in the transverse position in the superior lateral portion of the globe over the closed eyelid. The measurement is taken 3 mm behind the globe encompassing the width of the entire nerve from the margins of the dura mater on either side. Hypoechoic shadowing behind the globe can sometimes obscure the margins of the optic nerve sheath and care must be taken to avoid this artifact [85]. None. It is important that orbit settings are programmed into the ultrasound device because insonation with an inappropriately high acoustic power can lead to retinal injury. The application of excessive pressure over the orbit can lead to nausea, vomiting and vasovagal symptoms [85].

Curr Treat Options Neurol (2014) 16:297 Cost/cost effectiveness

Page 25 of 37, 297 Equipment and technical expertise are expensive, but each individual examination is relatively inexpensive.

Surgery &

Liver transplant Liver transplant is the definitive treatment for acute liver failure and hepatic encephalopathy. The probability of spontaneous recovery has a large impact on the decision to proceed with transplantation. Recovery is primarily predicted by the patient’s degree of encephalopathy (grade I II 65 % 70 % recovery, grade III 40 % 50 % recovery, grade IV G20 % spontaneous recovery) [86]. Age and the cause of liver failure also predict recovery. Transplant free survival rates are highest for those with liver failure because of acetaminophen poisoning, hepatitis A, ischemia, and pregnancy. Conversely, transplant free survival is lowest for those with hepatitis B, autoimmune hepatitis, Wilson disease, Budd-Chiari, and cancer. Among those who get transplanted, 1-year survival rates exceed 80 % [87]. The model for end-stage liver disease (MELD) score is standardly used to predict survival in patients with chronic liver failure and is used for liver transplant allocation for patients with chronic liver failure. The MELD score takes into account a patient’s serum bilirubin, INR and creatinine, but does not adjust for other comorbidities that may affect survival, such as chronic hepatic encephalopathy. Additional MELD points may be assigned for patients with complicating medical issues. Practitioners may petition their local transplant center and regional review board for additional MELD points that better reflects a patient’s risk of death without transplantation and improves their standing on the transplant waiting list. Neurologists may have a role in advocating for their patients with severe neurologic sequelae of liver failure in order to maximize a patient’s chance of a curative transplant [88].

Other treatments Renal replacement therapy Patients with cirrhosis and hepato-renal syndrome are particularly prone to encephalopathy because of the inability of the kidney to clear plasma ammonia. In addition, acute renal failure in the context of acute liver failure has been associated with a proinflammatory state and breakdown of the blood brain barrier, which may contribute to encephalopathy. Electrolyte abnormalities that can occur in the context of renal insufficiency including hyponatremia, hyperkalemia, secondary hyperthyroidism, and acidosis, can also lead to encephalopathy. Because 50 % of patients with acute liver failure suffer concomitant acute renal failure [31], utilization of dialysis can be an elegant way to both treat uremia and generate a hyperosmolar state to treat elevated ICP. This is achieved by using hypertonic saline replacement fluid if continuous veno-venous hemofiltration (CVVH) is used or by adjusting the sodium concentration in the dialysis bath. Pediatric studies of inborn errors of metabolism have shown that renal replacement therapy can lower blood ammonia levels. Recently, studies of extracorporeal albumin dialysis and

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Curr Treat Options Neurol (2014) 16:297 continuous renal replacement therapy with hemofiltration have been shown to lower arterial ammonia levels and improve HE in patients with acute liver failure [89, 90•]. Contraindications Lack of central line access. Complications

Line placement for renal replacement therapy may be complicated by bleeding, blood stream or procedure site infection, arterial puncture or pneumothorax. Intermittent hemodialysis can be complicated by dialysis disequilibrium, interstitial cerebral edema, and increased ICP related to rapid dialysis [91•, 92–95]. A urea gradient may be established during rapid dialysis causing brain urea content to exceed blood urea concentrations, causing an influx of water into brain cells resulting in cerebral edema. Alternately, sodium and potassium cations may be displaced from organic anions because of a relative acidotic milieu established during dialysis. These osmotically active moieties may lead to cerebral edema. In addition, intermittent hemodialysis can lead to volume shifts that may not be hemodynamically tolerated by liver failure patients with hypotension. A randomized trial of continuous vs intermittent renal replacement therapy in critically ill patients with acute liver and renal failure found improved cardiovascular stability and ICP parameters with continuous renal replacement [96].

Special points

In the context of baseline cerebral edema because of liver failure, or hypotension, slower renal replacement (either SLED or CVVHD) should be utilized [97].


Expensive (primarily because of staffing required for continuous renal replacement).

Hyperventilation Permissive hypercapnia should be avoided as this will elevate ICP. Similarly, inverse ratio ventilator modes with elevated pressure settings for a significant duration of the respiratory cycle may inhibit jugular venous outflow and lead to increased ICP. Many acute liver failure patients will spontaneously hyperventilate as part of an autoregulatory response [17]. This should not be treated unless the patient becomes extremely alkalotic (ie, pH 97.6). However, it should be kept in mind that alkalosis favor conversion of NH4+ to NH3, which more easily crosses the blood brain barrier. Conversely, induced hyperventilation is not recommended except in acute cases of herniation since this can lead to ischemia because of vasoconstriction. Maintenance of a PaCO2 between 30 and 40 mm Hg is reasonable. In circumstances of ongoing or impending herniation (eg, fixed dilated pupil/s, new onset intracranial hemorrhage with midline shift), it may be necessary to perform short-term hyperventilation. Reduction in PaCO2 by 1 mm Hg will reduce cerebral blood flow (CBF) by 3 %. Standard dosage The most efficient means of hyperventilation is manual bag mask ventilation at a rate of roughly 30 40 breaths per min for 3 5 min. Alternately, ventilator settings may be adjusted to a higher respiratory rate and/or tidal volume to achieve a PCO2 ≤25 mm Hg. Contraindications Main side effects

Ongoing cerebral ischemia or recent stroke is a relative contraindication since hyperventilation can lead to vasoconstriction and stroke expansion. Prolonged hyperventilation may lead to respiratory alkalosis. Because of the buffering capacity of the CSF, hyperventilation loses its efficacy over time.

Curr Treat Options Neurol (2014) 16:297 Special points


Page 27 of 37, 297 Hyperventilation is meant to be a short-term, stop gap treatment until a more definitive means of treating elevated ICP can be instituted. Though the ICP lowering effects of hyperventilation can be seen within seconds (eg, reversal of pupillary dilatation within seconds of hyperventilation), the durability of hyperventilation is limited to 1 to 24 h because of CSF buffering. Hyperventilation may serve as a bridge to osmotic therapy, CSF diversion (external ventricular drainage), decompressive surgery (removal of space occupying lesion such as a hematoma) or in the case of acute liver failure, definitive treatment with liver transplant. Inexpensive.

Hypothermia Induced hypothermia to 32 °C 34 °C can reduce CBF and ICP by reducing metabolic demand if metabolic coupling is intact. Every 1 °C reduction in temperature reduces cerebral oxygen metabolism (CMRO2) by 7 %. Hypothermia also reduces inflammation and has been shown to augment ICP management in patients with traumatic brain injury [98, 99]. Small studies utilizing hypothermia in the context of acute liver failure have suggested that it may be an effective strategy for ICP control as a bridge to transplant [100– 105]. Hypothermia has never been compared with induced normothermia (fever management) for ICP management. Contraindications Refractory hypotension, active bleeding, DIC, and septic shock. Complications

The most common side effect of hypothermia is shivering, which must be aggressively managed because it can increase metabolic demand and counteract the neuroprotective effects of hypothermia. Other complications include systemic infection, and bacteremia, coagulopathy, pneumonia, hypokalemia, and arrhythmias. Side effects of rewarming include pulmonary edema, systemic inflammatory response syndrome (SIRS) and rebound cerebral edema.

Emerging therapies Standard dosage Contraindications Main drug interactions

Main side effects

Special points

Initial dose 25 mg TID; Maintenance dose 50 100 mg TID; Maximum ≤60 kg: 50 mg TID, 960 kg 100 mg TID Hypersensitivity, DKA, cirrhosis, inflammatory bowel disease, bowel obstruction, or other intestinal absorption conditions. Because acarbose is a competitive inhibitor of pancreatic alpha amylase and inhibits metabolism and absorption of glucose, it can enhance hypoglycemic effects of other hypoglycemic drugs . MAO inhibitors, pegviosmant, salicylates, and SSRIs may enhance the hypoglycemic effect of acarbose. Neomycin may enhance the toxic effects of acarbose by diminishing its metabolism. Elevated transaminases, hypoglycemia, diarrhea, abdominal pain, and flatulence. Acarbose should not be used with renal insufficiency with a Cr 92 mg/dL. Acarbose is typically used in diabetes and acts to limit conversion of carbohydrates to monosaccharides and reduces proteolytic intestinal bacteria that produce ammonia. A randomized trial has shown improvement in early stage hepatic encephalopathy in those receiving acarbose [106].

297, Page 28 of 37


Cost/cost effectiveness Standard dosage Contraindications Main drug interactions Main side effects

Moderately expensive 5 g BID. Hypersensitivity. Probenecid may increase serum concentrations of sodium benzoate. Increased risk of infection, seizure, cerebral edema, fever, agitation, hypotension, vomiting, diarrhea, anemia, DIC, and respiratory distress.

Special points

Sodium benzoate is typically used for pediatric urea cycle disorders that result in elevated serum ammonia levels. Sodium benzoate reacts with glycine to form hippurate, which is renally excreted, thus lowering serum ammonia. A small randomized trial demonstrated improvements in encephalopathy that were similar to lactulose [107].


Inexpensive. Initial dose 0.2 mg over 15 30 seconds, may repeat 0.3 0.5 mg doses up to maximum dose of 3 mg within 1 h.

Contraindications Main drug interactions

Hypersensitivity to flumazanil or benzodiazepines, use of benzodiazepine for seizure control, and seizure disorder. Flumazenil may diminish the sedative effect of other hypnotics.

Main side effects

There is a U.S. FDA black box warning because benzodiazepine reversal with flumazenil may lead to seizures. Since flumazenil competitively inhibits GABA receptors, patients who develop seizures should be treated with medications that abort seizures via another mechanism. In intubated patients, propofol should be a first line therapy for flumazenil related seizures. In nonintubated patients leviteracetam (1000 mg IV) or lacosamide (200 mg IV) might be reasonable alternatives, though neither has been studied in the context of flumazenil induced seizures.

Special points

Excessive central GABAnergic tone and increase in benzodiazepine receptor ligands contribute to hepatic encephalopathy. Flumazenil is a benzodiazepine receptor antagonist and theoretically may improve hepatic encephalopathy. A systematic review of 12 randomized trials with 765 patients found a short-term benefit in hepatic encephalopathy symptoms compared with placebo, but no recovery or survival benefit [108]. Because of its short half-life, re-sedation may occur after metabolism. Flumazenil does not reverse the GABA effect of nonbenzodiazepine agonists such as ethanol or barbiturates.

Cost/cost effectiveness Standard dosage Contraindications

Inexpensive. Available as a dietary supplement. Used in doses ranging from 0.1 0.3 mg PO for sleep. None.


Melatonin concentrations can be affected by propranolol, 8methoxypsoralen, caffeine, and ethanol.

Main side effects

Daytime sleepiness, cognitive impairment, hypothermia, and hyperprolactinemia.

Special points


Melatonin levels may be altered in cirrhosis contributing to daytime sleepiness and encephalopathy. Melatonin supplementation may help restore normal sleep-wake cycles. Inexpensive.

Curr Treat Options Neurol (2014) 16:297 Standard dosage Contraindications

Page 29 of 37, 297 8 11 mg/d PO. None.


Zinc may decrease the serum concentration or absorption of ceftibuten, cephalexin, deferiprone, dolutegravir, eltombopag, quinolones, tetracyclines, and trientine.

Main side effects

Dizziness, headache, nausea, vomiting, diarrhea, and abdominal cramps. Administration of zinc without copper may cause low serum copper levels.

Special points

Zinc may enhance conversion of amino acids to urea and improve neurotransmission. Small randomized trials have not shown promising results [109].


Inexpensive 990 mg PO BID-TID or 50 mg/kg IV loading dose followed by 50 mg/kg in divided doses q 3 h. For patients with ESRD: 20 mg/kg after dialysis.

Contraindications

None


None.

Main side effects

New onset seizures and increased seizure frequency have been described with carnitine (both PO and IV). Other adverse reactions associated with IV administration include hypertension, chest pain, headache, dizziness, fever, hypercalcemia, diarrhea, nausea, vomiting, abdominal pain, anemia, weakness, paresthesias, rhinitis, and infection.

Special points

Animal data suggest that L-carnitine is protective against ammonia neurotoxicity. L-carnitine is frequently used for valproic acid associated hyperammonemia. In randomized placebo controlled trials of patients with hepatic encephalopathy, L-carnitine improved depression, anxiety, quality of life, physical function, cognitive function, ammonia, urea, and bilirubin levels [110, 111].


Inexpensive. Immediate release: 5 mg PO qd titrate up to 20 mg qd. Extended release: 7 mg PO qd, titrate up to maximum dose of 28 mg PO qd. Hypersensitivity. Carbonic anhydrase inhibitors and sodium bicarbonate may decrease excretion of memantine. Trimethoprim may enhance the risk of myoclonus or delirium related to memantine.

Main side effects

Confusion, dizziness, headache, anxiety, depression, and elevated alkaline phosphatase.

Special points

Excitotoxicity plays a role in hepatic encephalopathy, therefore NMDA antagonist memantine may improve hepatic encephalopathy [112–114].


Expensive. Start at 1 mg PO qd and titrate to 4 16 mg PO qd given in divided doses.

Contraindications

U.S. FDA black box warning states that ergot alkaloids are contraindicated with potent CYP3A4 inhibitors including azole antifungals, protease inhibitors and macrolides.


Methysergide is metabolized to its active metabolite methyergometrine. Other ergots and triptans should be used with caution with methysergide.

Main side effects

Ergotism (severe vasoconstriction) including myocardial ischemia, periph-

297, Page 30 of 37

Curr Treat Options Neurol (2014) 16:297 eral vascular ischemia, and stroke are feared side effects. Pleural and retroperitoneal fibrosis may occur. Ergotamines have been associated with cardiac valvular fibrosis. Special points

Cost/cost effectiveness Standard dosage Contraindications Main drug interactions Main side effects

Special points


Serotoninergic tone is thought to be increased in acute liver failure based on animal data. Methysergide is a nonselective serotonin receptor inhibitor that has shown some benefit in improving hepatic encephalopathy in a rat model. Methysergide is not currently marketed in the United States 50 mg PO qd or 380 mg IM every 4 weeks. Hypersensitivity, acute opioid withdrawal. None. May precipitate opioid withdrawal with hypertension, sweating, agitation and pain. Patients treated with naltrexone may have exaggerated responses to lower doses of opioids, placing them at risk for opiate overdose. Dose related hepatocellular injury (ALT elevation) may occur. Beta-endorphin and met-enkephalin levels are increased in liver failure. Naltrexone has been shown to improve motor activity in rats with hepatic encephalopathy [115]. IM doses is expensive; PO dosing is relatively inexpensive. 5 mcg/kg SQ × 5 days then every 3 days for a total of 12 doses Hypersensitivity to G-CSF. G-CSF may enhance the toxic effects of bleomycin or topotecan.

Main side effects

Elevated WBC count (9100,000/mm3) have been reported, which may place patients at risk for hyperviscosity related infarction. Allergic reactions, alveolar hemorrhage, cutaneous vasculitis, acute respiratory distress syndrome and splenic rupture have been reported.

Special points

Conceptually, G-CSF may mobilize bone marrow stem cells that may lead to hepatic regeneration. In a small randomized trial patients who received GCSF had higher 60 day survival and less hepatorenal syndrome, hepatic encephalopathy and sepsis, than those treated with placebo [116].

Cost/cost effectiveness Special points

Expensive. In a small retrospective study, embolization of spontaneous portosystemic shunts was found to improve hepatic encephalopathy in patients with sufficient liver reserve and refractory hepatic encephalopathy [117].

Cost/cost effectiveness Standard procedure

Expensive. Non-cell based (plasmapheresis, albumin dialysis, charcoal-based hemadsorption); Living hepatocyte based (bioartificial liver support systems using either human or porcine hepatocytes for detoxification and synthetic function).

Special points

A meta-analysis of 12 randomized controlled trials with 483 patients found no significant mortality benefit with artificial hepatic support systems compared with medical therapy, however, there may be some benefit in those with acute on chronic liver failure [118, 119]. Use of extracorporeal devices is generally restricted to clinical trials.


Very expensive. A smaller liver graft is placed next to the native liver or in the hepatic bed after a portion of the native liver is removed. This procedure allows for a


Page 31 of 37, 297 living donor transplant and may eliminate the need for chronic immunosuppression.


Very expensive. Transplant using pig liver has been attempted with limited success in the past but improved immunosuppression may make this option more attractive again, especially in light of limited organ supply.


Very expensive.

Pediatric considerations &

&

Diagnosing HE in children and neonates presents a greater challenge than in adults as agitation, infection, and electrolyte disturbances may present in a similar fashion. IN addition, assessment of mental status can be challenging at different developmental stages and may be confounded by developmental delay that may be inherent to the underlying disease process. Treatment of easily reversible confounders to the assessment of mental status (such as fever, infection and electrolyte disturbances) along with diagnostic investigations such as brain imaging (CT or MRI) and EEG may help guide the diagnosis of hepatic encephalopathy (triphasic waves). Hepatic encephalopathy occurs in the majority of pediatric patients with acute liver failure and is not a consistent indicator of prognosis.

Prognosis Prognosis is very tightly linked to the etiology of liver failure. Hepatic encephalopathy with acute liver failure because of acetaminophen overdose, pregnancy, or hepatitis A has a more favorable outcome than other etiolo-

Figure 3. Predictors of increased mortality without emergent transplant: King’s College Criteria [86].

297, Page 32 of 37

Curr Treat Options Neurol (2014) 16:297 gies, with transplant free survival approaching 50 % [120]. Spontaneous recovery is least likely with Wilson disease, nonacetaminophen idiosyncratic drug reactions, and indeterminate causes [121]. Patients who suffer acute liver failure because of antiepileptic medications have a significantly higher death rate after liver transplant than patients who have acute liver failure because of other drugs [122]. The most commonly used prognostic classification scheme, the King’s College Hospital criteria (Fig. 3), uses simple measures that negatively predict transplant free survival [86]. The Model for End-Stage Liver Disease or MELD Score is a prospectively developed chronic liver disease score that is currently used by UNOS to prioritize chronic liver failure patients for liver transplantation [123, 126]. The MELD score is calculated by the formula: MELD=3.8 [Ln serum bilirubin (mg/dL)] + 11.2 [Ln INR] + 9.6 [Ln serum creatinine (mg/dL)] + 6.4 where Ln is the natural logarithm. Three-month survival decreases precipitously with MELD scores greater than 20. Higher MELD scores correlate with decreased survival among patients with fulminant liver failure [124, 126].However, MELD scores do not seem to be more accurate than King’s College Criteria or INR alone [120, 125]. Overall, the predictive value of any modality, including the King’s College Hospital criteria, may be influenced by the interruption of the natural history of disease by transplant itself.

Compliance with Ethics Guidelines Conflict of Interest Jennifer A. Frontera declares that she has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.

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Management of covert hepatic encephalopathy.

Pathophysiology, diagnosis, and management of hepatic encephalopathy.

Management of hepatic encephalopathy in the hospital.

Contemporary Understanding and Management of Overt and Covert Hepatic Encephalopathy.

Advances in cirrhosis: Optimizing the management of hepatic encephalopathy.

Portosystemic shunt syndrome and endovascular management of hepatic encephalopathy.

Hepatic Encephalopathy.

Hepatic encephalopathy.

[Hepatic encephalopathy].

Hepatic encephalopathy.

Covert and Overt Hepatic Encephalopathy: Diagnosis and Management.

Neurochemistry of hepatic encephalopathy.

[Prevention of hepatic encephalopathy].

Hepatic encephalopathy: historical remarks.

Hepatic encephalopathy without cirrhosis.

Liver capsule: Hepatic encephalopathy.

Clinical neurophysiology of hepatic encephalopathy.

Challenges in diagnosing hepatic encephalopathy.

Dopamine agents for hepatic encephalopathy.

Encephalopathy in infantile hepatic cirrhosis.

Vancomycin in resistant hepatic encephalopathy.

Hepatic Encephalopathy in Liver Cirrhosis.

Benzodiazepine compounds and hepatic encephalopathy.

Plasma phenylethanolamine in hepatic encephalopathy.