1158 SECTION X Pediatric Critical Care Gastroenterology and Nutrition amatoxins NAC and silibinin have been suggested as potential therapies, although definitive trial data are lacking A full 50% of P[.]
1158 S E C T I O N X Pediatric Critical Care: Gastroenterology and Nutrition • BOX 96.3 Diagnostic Workup Hematology CBC with differential PT/INR Factor V level Factor VII level Fibrinogen level ABO/Rh typing Chemistry Electrolytes Calcium, magnesium, phosphorus BUN, creatinine Glucose Lactate, pyruvate Bilirubin conjugated and unconjugated AST, ALT GGT Alkaline phosphatase Cholesterol, triglycerides Ferritin Blood gases a-fetoprotein Acylcarnitine profile (children #3 mo) Amino acid quantitative Ceruloplasmin (children 3 y) Copper (children 3 y) b-hCG (females 12 y) Immunology IgG level Antinuclear antibody (children 3 y) Antismooth muscle antibody (children 3 y) Antiliver kidney microsomal antibody (children 3 y) Antineutrophil cytoplasmic antibody (children 3 y) Antisoluble liver antigen Soluble IL-2 receptor Microbiology HSV DNA Enterovirus DNA (children #3 mo) CMV DNA EBV DNA Varicella DNA Adenovirus DNA Parvovirus B19 DNA Toxoplasma IgG and IgM (children #3 mo) Hepatitis A IgM ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; CMV, cytomegalovirus; DNA, deoxyribonucleic acid; EBV, Epstein-Barr virus; GGT, g-glutamyltransferase; hCG, human chorionic gonadotropin; HSV, herpes simplex virus; IgG, immunoglobulin G; IgM, immunoglobulin M; IL, interleukin; INR, international normalized ratio; PT, prothrombin time amatoxins NAC and silibinin have been suggested as potential therapies, although definitive trial data are lacking A full 50% of PALFs due to mushroom poisoning have progressed to liver transplantation.30 Autoimmune Hepatitis Although autoimmune hepatitis usually presents as chronic liver disease, a small percentage will present with PALF Elevations in autoimmune antibodies (antinuclear antibody, antismooth muscle antibody, liver-kidney microsomal antibody, soluble liver antigen) and total IgG level can help decipher the diagnosis Liver biopsy is very helpful if it can be conducted safely If autoimmune hepatitis is suspected, initiation of intravenous corticosteroids can be expected to alter the course of disease progression and avoid the need for transplantation Wilson Disease Wilson disease (WD) in the setting of PALF can be a difficult diagnosis Serum ceruloplasmin may be falsely low in non-WD PALF due to poor synthetic function or falsely elevated due to acute-phase reaction in WD A Coombs-negative hemolytic anemia is almost always present along with an elevated serum bilirubin Transaminases and alkaline phosphatase may be relatively low and the ratios of alkaline phosphatase (in International Units per liter)/bilirubin (in milligrams per deciliter) less than and aspartate transaminase (AST)/alanine transaminase (ALT) greater than 2.2 may suggest the diagnosis.31 Mutational analysis is currently the most reliable method of making the diagnosis, but many centers not have the ability to get this testing completed in a timely manner to be helpful in the acute setting The WD score— which incorporates AST, serum bilirubin, white blood cell count, and PT—can be used to determine prognosis.32 Chelation therapy should be initiated with D-penicillamine or more commonly now with trientine Metabolic Disease Undiagnosed metabolic disorders account for about 10% of PALF patients, mostly in infants.18 Urea cycle defects can also present with the features of ALF early in life Speedy and reliable diagnosis can lead to early supportive care and appropriate treatment For some metabolic liver disease, such as fatty acid oxidation defects, medical management can be the mainstay of treatment, with liver transplantation as a last resort In diseases such as mitochondrial cytopathies, with multisystem involvement, transplantation will not alter nonhepatic disease progression and may be futile Pediatric Intensive Care Unit Complications and Management Neurologic Complications: Hepatic Encephalopathy and Cerebral Edema Neurologic status should be monitored clinically; classification of the stages of HE is based on clinical findings, which may be augmented by EEG changes32a,33 (see Box 96.3) Computed tomography (CT) scans are not generally useful early in encephalopathy other than as a baseline examination to be compared with subsequent imaging to evaluate for signs of cerebral edema later in the disease CT of the head without contrast can be beneficial to evaluate intracranial herniation or intracranial bleeding but is not especially sensitive to the degree of cerebral edema The mainstay for monitoring progression of encephalopathy is frequent serial neurologic examinations.34 Transcranial Doppler ultrasound is a noninvasive tool to monitor middle cerebral artery blood flow velocity Although not validated in children, some other noninvasive methods for ICP measurement used are optic nerve sheath diameter and near-infrared spectroscopy (NIRS) In adults, optic nerve sheath greater than mm is associated with increased ICP, while in children no clear threshold exists CHAPTER 96 Acute Liver Failure 1159 NIRS uses spectroscopic analysis of regional perfusion based on hemoglobin changes and correlates with risk for neurologic complications Biomarkers35—such as neuron-specific enolase, S100 beta found in astrocytes, or myelin basic protein found in oligodendrocytes—are increased after brain injury S100 beta and interleukin-6 are associated with HE in children Direct ICP monitoring is the most sensitive and specific measure of ICP, but increases the intracranial bleeding risk, has not been demonstrated to alter outcome, and the use of ICP monitors in PALF depends largely on individual center practices Acute HE is defined as changes in consciousness that occur as a result of acute hepatic dysfunction in the absence of other factors such as sedative medications, intracranial hemorrhage, or metabolic disturbances From the PALF-SG, HE was present in 50% of children upon admission into the study and increased to 65% during the subsequent days.18 The rate of progression is variable, but it may increase rapidly within hours of presentation to coma and be associated with the development of fatal cerebral edema Although trending ammonia can be helpful to indicate the trajectory of HE, the serum level does not predictably measure the degree of or development of HE Hyperreflexia is a relatively early sign of HE, while decorticate or decerebrate posturing are late signs of HE Drowsiness and lethargy or irritability and inconsolability become readily apparent as the patient progresses into stage II HE Inappropriate behavior with outbursts of anger or crying may develop Impaired motor coordination—such as ataxia, dysarthria, apraxia, hyperreflexia, sustained clonus, rigidity, extensor posturing, and bizarre facial expressions—become evident Stage III HE is distinguished by progressive somnolence and stupor The patient is arousable by vigorous physical stimuli but is disoriented, does not respond to commands, and does not recognize family members.13 Intubation and ventilation may be needed as the patient approaches grade III or if patients become combative and a danger to themselves or others Progression into stage IV HE is defined by the presence of coma The patient responds only to painful stimuli In deeper stage IV HE, the patient may exhibit decerebrate posturing with the loss of brainstem reflexes Acute HE is considered to be completely reversible after resolution of the hepatic dysfunction as long as cerebral edema and poor brain perfusion has not caused neuronal injury, although long-term neurodevelopmental studies are only now being conducted Management of Hepatic Encephalopathy and Cerebral Edema Cerebral Edema Glucose, Electrolytes, and Fluid Balance Cerebral edema may develop during or beyond stage III HE and progress within hours of onset of coma and contributes to risk of death following liver transplantation.11,36–39 The pathogenesis of cerebral edema involves the interaction of ammonia, other hepatic toxic metabolites, and altered cerebral blood flow Ammonia is a water-soluble molecule that crosses freely into the brain where it serves as a substrate for astrocyte glutamine synthase to convert glutamate to glutamine Glutamine acts as an active intracellular osmole leading to astrocyte swelling, osmotic cerebral edema, and increased ICP Homeostatic mechanisms attempt to maintain perfusion by increasing systemic vascular resistance Evidence also supports the belief that glutamine acts as a carrier of ammonia into the mitochondria, where the accumulation leads to oxidative stress and contributes to further to astrocyte swelling.40 The goal of fluid balance is to maintain hydration and renal function without worsening or provoking cerebral edema Fluid input should be 75% to 95% of normal maintenance requirements in normotensive patients Intravenous fluids and electrolytes— specifically potassium, phosphorus, calcium, and magnesium— should be monitored carefully and replaced if necessary Hypoglycemia may occur due to the failure of hepatocytes to sustain glucose synthesis and release compounded by hyperinsulinemia from diminished hepatic degradation and secondary bacterial infection.43–46 Frequent bedside monitoring of blood glucose concentrations and the intravenous administration of glucose may prevent this complication Hypoglycemia should be treated with titration of continuous glucose infusions The support of a nutritionist to help with energy calculations and parenteral therapy in the ICU setting is valuable Lactulose, a nonabsorbable disaccharide, may be administered orally or via nasogastric tube Lactulose is fermented by intestinal flora to lactic acid, acidifying the bowel contents, facilitating conversion of ammonia to ammonium ion and thus limiting its absorption The nonabsorbable antibiotic rifaximin is commonly used to reduce ammonia production by colonic bacteria, replacing the traditional use of enteral aminoglycoside antibiotics, particularly neomycin.41 Limiting protein intake to 0.5 to 1.0 g/ kg per day, whether enterally or parenterally, has also been recommended If the encephalopathy progresses to compromise respiratory drive, elective intubation and mechanical ventilation should be undertaken If sedation is required, either for restraint or during procedures, short-acting sedatives or opiates should be used at the smallest dose that will provide the desired effect and will allow safety of the child Benzodiazepines should be avoided because the g-aminobutyric acid (GABA) receptor has been implicated in the development of encephalopathy When cerebral edema is apparent, appropriate cerebral perfusion pressure for age should be maintained by using neuroprotective measures such as administering measured fluid, maintaining normoglycemia, permitting mild hypertension, avoiding hypoxemia, and elevating the head 20 to 30 degrees Although hyperventilation temporarily reduces ICP, the effect is not sustained and prolonged use is not recommended Hypertonic saline and mannitol have been used to lower increased ICPs.17 Serial measurements to avoid serum osmolality greater than 320 mOs/L are recommended, especially if there is evidence of renal compromise.42 Ventilation Although patients usually have normal pulmonary compliance at the onset of PALF, pulmonary edema and acute respiratory distress syndrome may develop as the disease progresses In this case, prompt mechanical ventilation will be required Ventilatory support is also required in all patients who progress to stage III encephalopathy and in some who, due to combativeness in stage II, are at risk of injuring themselves The need for support may be precipitated by the injudicious use of sedative medications, particularly benzodiazepines, that should be avoided in unventilated patients with PALF 1160 S E C T I O N X Pediatric Critical Care: Gastroenterology and Nutrition Urine output should be monitored for oliguria, whether from prerenal or renal causes If renal perfusion is adequate, loop diuretics and vasoactive-inotropic agents can be used to maintain urine output Should oliguria be unresponsive to additional fluids, early consideration should be given to renal replacement therapy (see Chapter 75) Central venous pressure monitoring is helpful for assessing and maintaining organ perfusion Inotropic support frequently becomes necessary in advanced liver failure with the onset of hypotension in association with multiple organ failure Permissive hypertension, especially in the setting of cerebral edema, may help maintain cerebral perfusion pressures Ascites Excessive peritoneal fluid accumulation can be found in many patients with PALF due to the combined effects of acute portal hypertension, lobular collapse, vasodilation, poor vascular integrity, and reduced oncotic pressure Clinically evident ascites occurs in less than half the patients but may be a site for secondary bacterial or fungal infection Treatment is rarely needed in the acute setting but includes albumin infusions and judicious use of diuretics Paracentesis may be indicated if peritonitis is suspected Renal Function Acute kidney injury from prerenal azotemia, acute tubular necrosis (ATN), and hepatorenal syndrome can complicate the course of PALF.47 Prerenal azotemia is commonly precipitated by dehydration and, more rarely, gastrointestinal bleeding A marked increase in blood creatinine concentration may develop from decreased glomerular filtration or increased muscle breakdown ATN is seen in the minority of patients and may occur because of hypovolemia Laboratory abnormalities indicating a diagnosis of ATN include abnormal urinary sediment, urinary sodium concentration greater than 20 mmol/L, reduction in creatinine clearance (urine/plasma creatinine ratio ,10), and oliguria (urine output ,0.5 mL/kg per hour) Hepatorenal syndrome is a common cause of renal insufficiency in adults with ALF but is unusual in PALF The pathophysiology is multifactorial, involving electrolyte imbalance, sepsis, and hypovolemia Laboratory evaluation reveals sodium retention (urinary sodium concentration ,20 mmol/L), normal urinary sediment, and reduced urinary output (,1 mL/kg per hour) The aim of renal management is to maintain circulating volume to prevent hypovolemia and ensure that urine output is greater than 0.5 mL/kg per hour without fluid overload If there are signs of oliguria, a volume expander can be given one time at 10 mL/kg If there are signs of fluid overload, the use of loop diuretics may be effective Severe oliguric renal failure often requires hemodialysis or continuous renal replacement therapy (CRRT; see Chapter 75) Although acute renal failure usually resolves quickly after liver transplantation, ATN may severely complicate the postoperative management.48,49 Even in patients who require hemodialysis or CRRT, renal function usually returns to normal after successful liver transplantation fibrinolytic factors (antithrombin III, protein C, and protein S).49,50 In PALF, impairment is evident in the actions of both clotting and fibrinolysis Often, administering vitamin K parenterally is trialed early on in the course to ensure that coagulopathy is not due to vitamin deficiency, but it rarely improves coagulation in PALF The PT and thus the INR depend immediately on the availability of factor VII, which has the shortest half-life of the clotting factors Measurement of factor VII may be a more sensitive indicator than the PT but is typically not as readily available Fibrinogen concentrations can also be decreased because intravascular coagulation is present in addition to factor deficiencies in almost all PALF patients, indicating ongoing thrombosis Sepsis may be present as an additional cause of disseminated intravascular coagulation (DIC) The use of thromboelastography (TEG) to assess the coagulation profile can be used to guide blood product transfusions In one study, this monitoring was associated with reduction in the volume of transfusions intraoperatively during the transplantation.50 Coagulopathy should be managed conservatively to avoid fluid overload Oozing from needle puncture sites and line insertion is common and usually should not necessitate transfusions Petechiae reflect decreased platelet function, disturbed vascular integrity, or DIC Treatment with fresh frozen plasma, cryoprecipitate, and platelet infusions is indicated for active bleeding and invasive procedures Spontaneous bleeding is unusual because both proand anticoagulation factors are deficient and no transfusion cutoff, in absence of bleeding, is supported by the literature Administration of recombinant factor VIIa may be useful in preparation for invasive procedures if coagulopathy is unresponsive to other blood products.51,53,54 Gastrointestinal tract hemorrhage secondary to gastritis or stress ulceration can be life threatening Proton pump inhibitors or high-dose histamine receptor antagonists should be administered intravenously to reduce the risk of upper gastrointestinal bleeding Infection Prophylaxis and Treatment The majority of adults and a lesser proportion of children develop infection that may be related to impairment of cellular and humoral immune systems from liver dysfunction.52,54,55 The organisms most often implicated are gram-positive bacteria, presumably of skin origin Gram-negative bacteria or a fungal infection is occasionally observed A diagnosis of sepsis should be considered in any patient with fever, with or without any other signs of infection Due to immune paralysis seen with advanced liver failure, symptoms of sepsis may be subtle and fever may be absent Accordingly, a high index of suspicion for sepsis should be maintained at all times Appropriate laboratory data, including pan cultures, should be obtained and treatment with broad-spectrum antibiotics should be initiated immediately, including antifungals when fungal infection is suspected Even in the absence of clinical infection, positive cultures from an indwelling catheter should be treated with appropriate antimicrobials, and the infected catheter should be removed Coagulopathy Liver Support The liver plays a crucial role in the synthesis of clotting factors (factors I or fibrinogen, II or prothrombin, V, VII, IX, and X) and Extracorporeal liver support (ECLS) for patients with ALF has a history that dates back before liver transplantation was an option CHAPTER 96 Acute Liver Failure However, despite clinical experiments with ex vivo liver perfusion or cross-circulation with human volunteers or animals, no evidence for increased survival was apparent.53a,56–59 In general, ECLS systems can be categorized as either purely nonbiologic filtration and detoxification systems or, with the addition of a cellular component designed to replace some of the synthetic function of the liver, biologic hepatic functional replacement CRRT has been used in patients with ALF for both hyperammonemia and associated acute kidney injury The timing and the dose of renal replacement is not well established However, early use of high dose renal replacement was associated with better survival in all patients with ALF.60 Use of dialysis for metabolic diseases causing hyperammonemia is well described and indicated to reduce dangerous levels in a short time frame For CRRT, the removal of ammonia depends on blood flow rate, hemofilter surface, and ultrafiltration rate Newer studies60 showed that CRRT could slow further deterioration and increase the likelihood of spontaneous recovery in children with PALF, and the degree of ammonia clearance within the first 48 hours of CRRT initiation directly influenced survival Although simple hemofiltration or dialysis can remove ammonia and other water-soluble molecules, a large number of potentially toxic hydrophilic and proteinbound molecules are not cleared To remove these substances, exchange transfusion, large volume plasma exchange, and dialysis with an albumin-containing dialysate have been undertaken Both to limit the waste of human-derived blood products and to improve the tolerability of the procedures, systems have been designed to remove the toxins by passing the separated blood fractions through activated charcoal or resin columns and returning the “cleaned” fraction to the patient in closed recycling systems, such as the molecular absorbent recirculating system (MARS), using albumin dialysis, and Prometheus, which uses plasma fractionation Bioartificial liver devices differ from toxin removal systems in that they contain a cell-housing bioreactor, which contains functional liver cells to replace the function of the damaged liver Two such systems that have undergone randomized control trials are HepatAssist and the Extracorporeal Liver Assist Device (ELAD) HepatAssist uses porcine hepatocytes in conjunction with plasmapheresis, toxin absorption, and an oxygenator In contrast, ELAD uses HepG2 cells, a hepatoblastoma-derived immortalized cell line, along with hemofiltration, toxin absorption, and an oxygenator Neither system is currently available for further clinical trials, but development continues.61,62 Decision-Making for Liver Transplantation for Acute Liver Failure ALF in childhood is a rare and potentially devastating medical condition Undoubtedly, many children have had their lives saved by timely liver transplantation Because of the rapidity of progression, organ allocation has been made a priority for these cases in most, if not all, allocations systems, exemplified in the United States by United Network for Organ Sharing (UNOS) status 1A The difficulty arises when trying to decide which child will not survive without liver transplantation Children with advanced encephalopathy, meeting all UNOS criteria for listing at status 1A, have survived with their native liver In the PALF database, there are cases of children listed for liver transplantation for PALF who would have undergone transplantation had an organ become available during the peak of their illness only to have subsequently recovered fully This dilemma lies behind all attempts to generate predictive models in PALF To quote Dr Robert Squires: “the 1161 dynamic nature of PALF challenges our ability to predict outcome.”59 The development of models incorporating disease progression have shown promise However, it has also been shown that most listing decisions for children with PALF are made early in their course at the transplant center before the dynamics of progression are seen to play out.61,62 It is encouraging that the incidence of transplantation for ALF in children, at least at active PALF study centers, has diminished with subsequent cohorts, with no detriment to overall patient survival.62 However, it is essential that work to reliably predict death without transplant for children with ALF continue It should be noted that the UNOS criteria63 allowing listing at status 1A for fulminant hepatic failure—that is, Policy 9.1.B.2.a.iii, “an international normalized ratio (INR) greater than 2.0”—does not predict mortality A much deeper level of consideration is required when making a decision to list any child with acutely deteriorating liver function Key References Squires Jr RH Acute liver failure in children Semin Liver Dis 2008;28:153-166 Lee WM Acute liver failure N Engl J Med 1993;329:1862-1872 Bhaduri BR, Mieli-Vergani G Fulminant hepatic failure: pediatric aspects Semin Liver Dis 1996;16:349-355 Schiff ER, Sorrell MF, Maddrey WC Schiff’s Diseases of the Liver 10th ed Philadelphia, PA: Lippincott Williams & Wilkins; 2007 Whitington PF, Alonso EM Fulminant hepatitis in children: evidence for an unidentified hepatitis virus J Pediatr Gastroenterol Nutr 2001;33:529-536 Alper G, Jarjour IT, Reyes JD, Towbin RB, Hirsch WL, Bergman I Outcome of children with cerebral edema caused by fulminant hepatic failure Pediatr Neurol 1998;18:299-304 Stravitz RT, Kramer DJ Management of acute liver failure Nat Rev Gastroenterol Hepatol 2009;6:542-553 Dhawan A Etiology and prognosis of acute liver failure in children Liver Transpl 2008;14(suppl 2):S80-S84 Squires Jr RH, Shneider BL, Bucuvalas J, et al Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group J Pediatr 2006;148:652-658 Lu BR, Zhang S, Narkewicz MR, et al Evaluation of the liver injury unit scoring system to predict survival in a multinational study of pediatric acute liver failure J Pediatr 2013;162:1010-1016.e1-e4 Hussain E, Grimason M, Goldstein J, et al EEG abnormalities are associated with increased risk of transplant or poor outcome in children with acute liver failure J Pediatr Gastroenterol Nutr 2014;58(4):449-456 Hunt A, Tasker RC, Deep A Neurocritical care monitoring of encephalopathic children with acute liver failure: a systematic review Pediatr Transplant 2019;23:e13556 Munoz SJ, Stravitz RT, Gabriel DA Coagulopathy of acute liver failure Clin Liver Dis 2009;13:95-107 Brown JB, Emerick KM, Brown DL, Whitington PF, Alonso EM Recombinant factor VIIa improves coagulopathy caused by liver failure J Pediatr Gastroenterol Nutr 2003;37:268-272 Squires RH Living donor liver transplant in pediatric acute liver failure: an important option, but when we use it? J Pediatr Gastroenterol Nutr 2014;58(1):1-2 Deep A, Stewart CE, Dhawan A, Douiri A Effect of continuous renal replacement therapy on outcome in pediatric acute liver failure Crit Care Med 2016;44:1910-1919 Li R, Belle SH, Horslen S, et al Clinical course among cases of acute liver failure of indeterminate diagnosis J Pediatr 2016;171:163-170 Squires JE, Rudnick DA, Hardison RM, et al Liver transplant listing in pediatric acute liver failure: practices and participant characteristics Hepatology 2018;68(6):2338-2347 The full reference list for this chapter is available at ExpertConsult.com e1 References Squires Jr RH Acute liver failure in children Semin Liver Dis 2008;28:153-166 Lee WM Acute liver failure N Engl J Med 1993;329:1862-1872 Bhaduri BR, Mieli-Vergani G Fulminant hepatic failure: pediatric aspects Semin Liver Dis 1996;16:349-355 Schiff ER, Sorrell MF, Maddrey WC Schiff’s Diseases of the Liver 10th ed Philadelphia, PA: Lippincott Williams & Wilkins; 2007 Whitington PF, Alonso EM Fulminant hepatitis in children: evidence for an unidentified hepatitis virus J Pediatr Gastroenterol Nutr 2001;33:529-536 Zakim D, Boyer TD Hepatology: A Textbook of Liver Disease 4th ed Philadelphia, PA: Elsevier; 2003 Alper G, Jarjour IT, Reyes JD, Towbin RB, Hirsch WL, Bergman I Outcome of children with cerebral edema caused by fulminant hepatic failure Pediatr Neurol 1998;18:299-304 Ee LC, Shepherd RW, Cleghorn GJ, et al Acute liver failure in children: a regional experience J Paediatr Child Health 2003;39:107-110 Arya R, Gulati S, Deopujari S Management of hepatic encephalopathy in children Postgrad Med J 2010;86:34-41; quiz 40 10 Kobayashi S, Ochiai T, Hori S, et al Complete recovery from fulminant hepatic failure with severe coma by living donor liver transplantation Hepatogastroenterology 2003;50:515-518 11 Stravitz RT Critical management decisions in patients with acute liver failure Chest 2008;134:1092-1102 12 Stravitz RT, Kramer DJ Management of acute liver failure Nat Rev Gastroenterol Hepatol 2009;6:542-553 13 Suchy FJ, Sokol RJ, Balistreri WF Liver Disease in Children 4th ed Cambridge: Cambridge University Press; 2014 14 Pineiro-Carrero VM, Pineiro EO Liver Pediatrics 2004;113(suppl 4): 1097-1106 15 Dhawan A Etiology and prognosis of acute liver failure in children Liver Transpl 2008;14(suppl 2):S80-S84 16 Horslen S Acute liver failure and transplantation in children S Afr Med J 2014;104(11 Pt 2):808-812 17 Mieli-Vergani G, Vergani D Autoimmune hepatitis in children: what is different from adult AIH? Semin Liver Dis 2009;29:297-306 18 Squires Jr RH, Shneider BL, Bucuvalas J, et al Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group J Pediatr 2006;148:652-658 19 Chapin CA, Mohammad S, Bass LM, Taylor SA, Kelly S, Alonso EM Liver biopsy can be safely performed in pediatric acute liver failure to aid in diagnosis and management J Pediatr Gastroenterol Nutr 2018;67(4):441-445 20 Mack CL, Ferrario M, Abecassis M, Whitington PF, Superina RA, Alonso EM Living donor liver transplantation for children with liver failure and concurrent multiple organ system failure Liver Transpl 2001;7:890-895 21 Ichai P, Legeai C, Francoz C, et al Patients with acute liver failure listed for superurgent liver transplantation in France: reevaluation of the Clichy-Villejuif criteria Liver Transpl 2015;21:512-523 22 Lu BR, Zhang S, Narkewicz MR, et al Evaluation of the liver injury unit scoring system to predict survival in a multinational study of pediatric acute liver failure J Pediatr 2013;162:1010-1016.e1-e4 23 Rajanayagam J, Frank E, Shepherd RW, Lewindon PJ Artificial neural network is highly predictive of outcome in paediatric acute liver failure Pediatr Transplant 2013;17:535-542 24 Azhar N, Ziraldo C, Barclay D, et al Analysis of serum inflammatory mediators identifies unique dynamic networks associated with death and spontaneous survival in pediatric acute liver failure PLoS One 2013;8:e78202 25 Anderson IB, Mullen WH, Meeker JE, et al Pennyroyal toxicity: measurement of toxic metabolite levels in two cases and review of the literature Ann Intern Med 1996;124:726-734 26 Duncan CC, Ment LR, Shaywitz BA Evaluation of level of consciousness by the Glasgow coma scale in children with Reye’s syndrome Neurosurgery 1983;13:650-653 27 Sussman NL, Lake JR Treatment of hepatic failure–1996: current concepts and progress toward liver dialysis Am J Kidney Dis 1996; 27:605-621 28 Letschert K, Faulstich H, Keller D, Keppler D Molecular characterization and inhibition of amanitin uptake into human hepatocytes Toxicol Sci 2006;91:140-149 29 Magdalan J, Ostrowska A, Piotrowska A, et al alpha-Amanitin induced apoptosis in primary cultured dog hepatocytes Folia Histochem Cytobiol 2010;48:58-62 30 Karvellas CJ, Tillman H, Leung AA, et al Acute liver injury and acute liver failure from mushroom poisoning in North America Liver Int 2016;36:1043-1050 31 Schilsky ML Wilson disease: current status and the future Biochimie 2009;91:1278-1281 32 Dhawan A, Taylor RM, Cheeseman P, De Silva P, Katsiyiannakis L, Mieli-Vergani G Wilson’s disease in children: 37-year experience and revised King’s score for liver transplantation Liver Transpl 2005;11:441-448 33 Hussain E, Grimason M, Goldstein J, et al EEG abnormalities are associated with increased risk of transplant or poor outcome in children with acute liver failure J Pediatr Gastroenterol Nutr 2014; 58(4):449-456 33a O’Brien CJ, Wise RJ, O’Grady JG, Williams R Neurological sequelae in patients recovered from fulminant hepatic failure Gut 1987;28:93-95 34 Hunt A, Tasker RC, Deep A Neurocritical care monitoring of encephalopathic children with acute liver failure: a systematic review Pediatr Transplant 2019;23:e13556 35 Toney NA, Bell MJ, Belle SH, et al Hepatic encephalopathy in children with acute liver failure: utility of serum neuromarkers J Pediatr Gastroenterol Nutr 2019;69:108-115 36 Blei AT Brain edema and portal-systemic encephalopathy Liver Transpl 2000;6(4 suppl 1):S14-S20 37 Jalan R Intracranial hypertension in acute liver failure: pathophysiological basis of rational management Semin Liver Dis 2003;23: 271-282 38 Blei A Hypothermia for fulminant hepatic failure: a cool approach to a burning problem Liver Transpl 2000;6:245-247 38a Scott TR, Kronsten VT, Hughes RD, Shawcross DL Pathophysiology of cerebral oedema in acute liver failure World J Gastroenterol 2013;19:9240-9255 39 Iadevaia MD, Prete AD, Cesaro C, Gaeta L, Zulli C, Loguercio C Rifaximin in the treatment of hepatic encephalopathy Hepat Med 2011;3:109-117 40 Mohsenin V Assessment and management of cerebral edema and intracranial hypertension in acute liver failure J Crit Care 2013;28:783-791 41 Vilstrup H, Iversen J, Tygstrup N Glucoregulation in acute liver failure Eur J Clin Invest 1986;16:193-197 42 Harry R, Auzinger G, Wendon J The clinical importance of adrenal insufficiency in acute hepatic dysfunction Hepatology 2002;36: 395-402 43 Clark SJ, Shojaee-Moradie F, Croos P, et al Temporal changes in insulin sensitivity following the development of acute liver failure secondary to acetaminophen Hepatology 2001;34:109-115 44 Walsh TS, Wigmore SJ, Hopton P, Richardson R, Lee A Energy expenditure in acetaminophen-induced fulminant hepatic failure Crit Care Med 2000;28:649-654 45 Mackelaite L, Alsauskas ZC, Ranganna K Renal failure in patients with cirrhosis Med Clin North Am 2009;93:855-869, viii 46 Kiser TH, Maclaren R, Fish DN Treatment of hepatorenal syndrome Pharmacotherapy 2009;29:1196-1211 47 Brown Jr RS, Lombardero M, Lake JR Outcome of patients with renal insufficiency undergoing liver or liver-kidney transplantation Transplantation 1996;62:1788-1793 48 Gimson AE, O’Grady J, Ede RJ, Portmann B, Williams R Late onset hepatic failure: clinical, serological and histological features Hepatology 1986;6:288-294 ... during the subsequent days.18 The rate of progression is variable, but it may increase rapidly within hours of presentation to coma and be associated with the development of fatal cerebral edema... Electrolytes, and Fluid Balance Cerebral edema may develop during or beyond stage III HE and progress within hours of onset of coma and contributes to risk of death following liver transplantation.11,36–39... monitoring of blood glucose concentrations and the intravenous administration of glucose may prevent this complication Hypoglycemia should be treated with titration of continuous glucose infusions