4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&searchT… 1/16

Official reprint from UpToDate www.uptodate.com ©2015 UpToDate

AuthorRobert H Squires, Jr, MD, FAAP

Section EditorElizabeth B Rand, MD

Deputy EditorAlison G Hoppin, MD

Acute liver failure in children: Management

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Mar 2015. | This topic last updated: Jul 31, 2014.

INTRODUCTION — Pediatric acute liver failure (PALF) is a complex, rapidly progressive clinical syndrome that isthe final common pathway for many disparate conditions, some known and others yet to be identified [1­3]. Theestimated frequency of acute liver failure (ALF) in all age groups in the United States is about 17 cases per 100,000population per year, but the frequency in children is unknown. PALF accounts for 10 to 15 percent of pediatric livertransplants performed in the United States annually.

PALF is a rapidly evolving clinical condition. There are no adequately powered studies to inform diagnosticalgorithms, to assess markers of disease severity and trajectory, and to guide decisions about liver transplant. Theclinician must construct an individualized diagnostic approach and management strategy. Management requires amultidisciplinary team involving the hepatologist, critical care specialist, and liver transplant surgeon.

Management of PALF and its complications in children are discussed here. An organized approach to diagnosingthe cause of PALF is presented separately. (See "Acute liver failure in children: Etiology and evaluation".)

ALF in adults is addressed in separate reviews. (See "Acute liver failure in adults: Etiology, clinical manifestations,and diagnosis" and "Acute liver failure in adults: Management and prognosis".)

GENERAL MANAGEMENT PRINCIPLES — After the initial characterization of the patient presentation, properpatient management needs to be conducted along multiple parallel paths [2,3]:

Clinical setting — Management of PALF requires admission to a highly skilled nursing environment (in mostcases, a pediatric intensive care unit), which allows close monitoring, particularly for changes in mental status.Careful and frequent bedside assessment by an experienced nurse or clinician is essential, and cannot be replacedby indirect monitors such as a cardiorespiratory and oxygen saturation monitor. Care givers must carefully examinethe child multiple times during the day and night to assess evidence of changing mental status or hepaticencephalopathy, increased respiratory effort, changing heart rate or changes in blood pressure that might be signsof infection, increasing cerebral edema, or electrolyte imbalance. Fluid balance (input and output) should be strictlymonitored.

Laboratory monitoring — Laboratory monitoring should include a complete blood count, electrolytes, renalfunction tests, glucose, calcium, phosphorous, ammonia, coagulation profile, total and direct bilirubin, and bloodcultures [3]. The frequency of laboratory monitoring should be at least daily, but multiple tests obtained regularlythroughout the day may be necessary to monitor the dynamic changes that can occur in PALF.

For measurement of ammonia, arterial samples are ideal but not always clinically practical. For children with stage0 to II hepatic encephalopathy (HE), ammonia can generally be monitored with venous samples obtained from afree­flowing catheter, and promptly placed on ice and transported to the laboratory. Children with more advanced HE

®®

Evaluate the cause of pediatric acute liver failure (PALF), guided by the patient’s age and prioritizing thediagnosis of treatable disorders (see "Acute liver failure in children: Etiology and evaluation")

Monitor the function of each organ system

Identify and treat complications

Provide medical support to maximize health and survival

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&searchT… 2/16

often require elective intubation and ventilatory support accompanied by placement of an arterial catheter. Ifavailable, ammonia samples should be obtained from the arterial catheter, but the arterial catheter should not beplaced solely for ammonia testing.

Laboratory studies for diagnosing the cause of the PALF are also important, and should be planned based on thepatient’s age and presentation, prioritizing those diagnoses that may be amenable to specific treatment. (See"Acute liver failure in children: Etiology and evaluation", section on 'Laboratory testing'.)

Fluids — If the child is in shock, fluid resuscitation and pressor support is needed to stabilize cardiovascularstatus. However, as a general rule, intravenous and oral fluid intake should be modestly restricted for most patientswith PALF. Total daily fluid intake (including medications and blood products) should initially be restricted tobetween 85 to 95 percent of the maintenance fluid requirement. Patients with PALF are sensitive to fluid volume andcan develop pulmonary and peripheral edema if they receive excessive fluid. At the same time, the serum glucoseshould be maintained between 90 and 110 mg/dL. Therefore, a central venous catheter may be required ifconcentrations of intravenous glucose over 12.5 percent are needed to maintain the serum glucose while restrictingfluid volume. Adjustment in fluid rates is based upon the clinical conditions.

CENTRAL NERVOUS SYSTEM

Encephalopathy — Hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with hepaticdysfunction. In a large registry of patients with pediatric acute liver failure (PALF), some degree of encephalopathywas present on admission in 50 percent of patients, and developed within the next seven days in an additional 15percent [1].

HE is determined by serial clinical evaluations of behavior, cognition, neurological examination, and, occasionally,electroencephalogram (EEG) to categorize the patient into one of five clinical stages of encephalopathy, rangingfrom stage 0 (minimal or no evidence of neurological dysfunction) to stage IV (coma) [4]. Stages of encephalopathyare defined slightly differently in infants and children up to 48 months of age (table 1) as compared with olderchildren and adults (table 2 and figure 1). Clinical staging of HE was originally developed to assess patients withcirrhosis rather than acute liver failure (ALF). Nonetheless, the scoring system has been found to have importantclinical and prognostic implications in adults and children with ALF. The pathogenesis and diagnosis of HE inadults is discussed in separate topic reviews. (See "Hepatic encephalopathy in adults: Clinical manifestations anddiagnosis" and "Hepatic encephalopathy: Pathogenesis".)

The role of other modalities to assess neurological function, such as visual evoked potentials, transcranial Doppler,cerebral near infrared spectroscopy (NIRS), and biomarkers, in the detection of HE is unclear at the present time.While neurologic morbidity remains a major determinant of outcome following pediatric ALF, further studies areneeded to improve early detection of neurologic injury, standardize management of seizures and HE, and todetermine whether such interventions improve outcomes.

Hepatic encephalopathy is not always clinically apparent in infants and young children. Distinguishing hepaticbased encephalopathy from other causes of an altered mental status such as sepsis, hypotension, electrolytedisturbances, hypoglycemia, anxiety, or “intensive care unit (ICU) psychosis” is difficult for all age groups.Hyperammonemia plays a central role in the development of HE in most cases. However, a specific level ofammonia does not result in a predictable degree of encephalopathy.

Initial treatment of HE includes minimizing excess stimulation, head elevation up to 30 degrees, initial restriction ofprotein intake to no more than 1 g/kg/day, treating suspected sepsis, and, if possible, removing sedativemedications that might affect mental status. For patients with progressive HE, we suggest medical therapy withlactulose, which is used empirically although there is only weak evidence to suggest that it is effective. The startingdose of lactulose is 0.4 to 0.5 g/kg every two hours by mouth or via nasogastric tube, with the dose adjusted asneeded to produce two to three soft stools daily [5]. Bowel “decontamination” with rifaximin or neomycin can beused as a second­tier treatment, but ototoxicity and nephrotoxicity are potential risks when neomycin is used.Medical management of HE has not been studied in children, and practices are extrapolated from the clinical

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&searchT… 3/16

experience in adults. (See "Hepatic encephalopathy in adults: Treatment".)

Some patients with HE develop a clinically important increase in intracranial pressure, which can have devastatingconsequences. Direct monitoring of intracranial pressure is the most sensitive and specific procedure to use whencompared with less invasive neuroradiographic procedures, such as cranial computed tomography (CT) ortranscranial ultrasonography. (See 'Cerebral edema' below.)

Children with ALF may experience generalized or focal seizures, or nonconvulsive (electrographic) seizures (NCS).In most cases, treatment begins with phenytoin, but practices are variable and there is no definitive standard ofcare. For seizures which are refractory to phenytoin, therapeutic options may include midazolam infusion,phenobarbital, levetiracetam, or topiramate. The selection of drug depends on the patient’s mental status,physiologic stability, availability of EEG monitoring to titrate drug infusions, and institutional experience.

Cerebral edema — Cerebral edema is a life threatening complication of ALF. It may lead to ischemic and hypoxicbrain injury, or brainstem herniation and death [6]. It occurs most commonly in those with advanced hepaticencephalopathy (stage III or IV) and can progress rapidly. Detection of cerebral edema in the early stages isdifficult, because noninvasive monitoring with clinical assessment or radiographic studies lacks sensitivity. Themost sensitive measure of intracranial pressure (ICP) requires surgical placement of an ICP monitor. However, ICPmonitor placement requires adequate cranial calcification and cannot be used in infants; therefore it is not acommon practice at most pediatric centers. Reported risks include bleeding in 10 and 20 percent, although theamount of bleeding is often minimal [7]. Once the ICP monitor is in place and properly functioning, it can be avaluable tool to continually assess response to ICP and its treatment [8]. The ICP monitor is also felt to be valuableduring surgical procedures, including liver transplantation, to gauge fluid and medical management of theunconscious patient. Monitoring of intracranial pressure in children remains controversial due to associatedcomplications of the procedure and lack of evidence that monitoring improves survival. The indications, types, andcomplications of ICP pressure monitoring in adults are discussed in a separate topic review. (See "Acute liverfailure in adults: Management and prognosis", section on 'Intracranial pressure monitoring'.)

The pathogenesis of cerebral edema is complex, involving the interaction among ammonia, cerebral blood flow, andinflammation [9]. Elevated levels of ammonia are generated as a consequence of the failing liver, which leads toincreased intracerebral concentrations. Ammonia enters the astrocyte, which is rich in glutamine synthetase.Conversion of ammonia and glutamate to glutamine, a potent intracellular osmolyte, results in an osmotic gradientthat favors astrocyte swelling that contributes to cerebral edema and intracranial hypertension. Changes in theinflammatory milieu, sepsis, fluid or blood product administration, and other factors can result in a sudden and oftenunanticipated increase in intracranial pressure.

Management of cerebral edema involves meticulous supportive care to maintain the following goals [9]:

Therapies targeted specifically to improve cerebral edema have not met scientific rigor, but they include hypertonicsaline to maintain serum sodium between 145 and 150 mEq/L, and mannitol keeping serum osmolarity less than320 mOsm/L to create a more favorable osmotic gradient to extract water from the brain. Hypothermia has beenused in adults with acute liver failure with some success, but has not been studied in children. (See "Acute liverfailure in adults: Management and prognosis", section on 'Treatment of intracranial pressure elevation'.)

HEMATOLOGIC

Coagulopathy — The prothrombin time (PT) and international normalization ratio (INR) are used to assess the

Oxygen saturation above 95 percentTotal daily fluid between 85 and 90 percent of maintenanceDiastolic pressure >40 mmHgAdequate sedationHead elevation of 20° to 30°Consideration of empiric broad spectrum antibiotics to minimize the development of bacterial infection

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&searchT… 4/16

severity of liver injury in the setting of acute liver failure (ALF), because these tests reflect hepatic production ofclotting factors, particularly factors V and VII, which have the shortest half­lives. However, the PT and INR are notgood markers for the risk of bleeding in patients with ALF. This is because ALF reduces both procoagulant proteins(eg, factor V, VII, X, and fibrinogen) and anticoagulant proteins (eg, antithrombin, protein C, and protein S) [2,3].(See "Coagulation abnormalities in patients with liver disease".)

This balanced reduction in the procoagulant and anticoagulant proteins may account for the relative infrequency ofclinically important bleeding in the pediatric acute liver failure (PALF) patient in the absence of a provocative eventsuch as infection or increased portal hypertension. A single dose of vitamin K should be administered once toinitially assess response of the coagulation profile. However, daily administration of vitamin K is unnecessary.Efforts to “correct” the PT/INR with plasma or other procoagulation products such as recombinant Factor VII shouldbe avoided. Correction of the PT/INR should be limited to patients with active bleeding or in anticipation of aninvasive surgical procedure.

Aplastic anemia — Bone marrow failure, characterized by a spectrum of features ranging from mild pancytopeniato aplastic anemia, occurs in a significant minority of children with ALF [10]. It is identified most commonly in thesetting of indeterminate PALF and may not be clinically evident until after emergent liver transplantation or recoverywithout transplantation. A possible association with human herpesvirus 6 (HHV6) has been suggested, but notestablished. (See "Acute liver failure in children: Etiology and evaluation", section on 'Infection with viruses otherthan hepatitis viruses'.)

Treatment includes immunomodulatory medications that include steroids, cyclosporine A, and antilymphocyte orantithymocyte globulin, as well as hematopoietic stem cell transplant.

GASTROINTESTINAL

Ascites — Ascites develops in some but not all patients with acute liver failure (ALF). Precipitating factors includehypoalbuminemia, excessive fluid administration, and infection. The primary treatment is moderate fluid restriction.Diuretics should be reserved for patients with respiratory compromise or generalized fluid overload. Overlyaggressive diuresis may precipitate hepatorenal syndrome. (See 'Renal' below.)

Bleeding — Gastrointestinal bleeding is surprisingly infrequent, given the degree of coagulopathy. This is probablybecause of a balanced reduction in the procoagulant and anticoagulant proteins, described above. (See'Coagulopathy' above.)

Prophylactic use of acid­reducing agents is often initiated when the patient is admitted, but their usefulness isdifficult to assess. Causes for bleeding include gastric erosions or ulcers due to nonsteroidal anti­inflammatorydrugs (NSAIDs), or idiopathic gastroduodenal ulceration. Infection can precipitate bleeding in this vulnerablepopulation, so blood cultures and initiation of antibiotics should also be considered when bleeding develops.Administration of platelets, blood, and plasma is necessary if bleeding is hemodynamically significant.

Pancreatitis — Biochemical and clinical pancreatitis is increasingly recognized as a condition associated withmultisystem failure in critically ill children. In patients who develop pancreatitis in the setting of acute liver failure,glucose and fluid management may become even more challenging.

RENAL — Patients with evidence of renal insufficiency and acute liver failure (ALF) on admission should beassessed for evidence of a medication or toxin as the precipitating cause (including acetaminophen, inhaledsolvents, mushrooms, recreational drugs, or medication induced pediatric acute liver failure [PALF]). During thehospital course, prerenal azotemia can develop if fluid restriction is too excessive for the patient’s needs. Acutedeterioration of renal function after presentation with ALF may result from systemic hypotension due to sepsis orhemorrhage.

Hepatorenal syndrome (HRS) is a feared renal complication associated with ALF, although it occurs morecommonly in the setting of chronic liver disease with established cirrhosis. The diagnosis is suspected when thereis evidence of deteriorating renal function in the absence of bleeding, hypotension, sepsis, or nephrotoxic

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&searchT… 5/16

medications. Unlike prerenal azotemia, the urine sodium typically is low, and there is no improvement with volumeexpansion. It can progress rapidly over the course of two weeks (type 1 HRS) or more slowly (type II HRS) [2].Renal replacement therapy with continuous venovenous hemofiltration or dialysis may be necessary in somecases, but only liver transplantation can reverse HRS.

METABOLIC — Metabolic abnormalities often seen in patients with acute liver failure (ALF) include [3]:

INFECTIOUS — Patients with acute liver failure (ALF) are susceptible to bacterial infection and sepsis because ofimmune system dysfunction [2]. Evidence of infection may be subtle, such as tachycardia, gastrointestinalbleeding, reduced renal output, or changes in mental status. Fever may or may not be present.

Thus, blood cultures should be obtained with any evidence of clinical deterioration, and antibiotics should beinitiated to cover both gram positive and gram negative organisms [12].

CARDIOPULMONARY — Excessive fluid administration contributes to pulmonary edema and should be avoided.For patients who develop pulmonary edema, careful fluid restriction and discrete use of diuretics may be needed insome instances, but should be used with caution because these interventions can reduce organ perfusion andprecipitate renal failure. Central venous pressure monitoring may assist in assessing volume needs for the child.Ionotropic support may be needed to maintain perfusion of vital organs.

NUTRITION — Nutrition support should be maintained to avoid a catabolic state. If it is not safe for the child toreceive oral or enteral feeding, intravenous alimentation (parenteral nutrition [PN]) should be initiated. (See"Parenteral nutrition in infants and children".)

We suggest the following parameters for PN in patients with pediatric acute liver failure (PALF):

LIVER SUPPORT — A number of approaches are being developed to perform some functions of the liver in anattempt to delay or avoid the need for liver transplantation. These include artificial hepatic assist devices (eg, themembrane­adsorbent recirculating system [MARS]). To date, none have been established as a valuable treatmentfor acute hepatic failure. (See "Acute liver failure in adults: Management and prognosis", section on 'Artificial

Hypoglycemia – Hypoglycemia is caused by impaired hepatic gluconeogenesis and depleted glycogenstores. Hypoglycemia is treated with continuous infusion of glucose, which is infused via a central venouscatheter to accommodate the hypertonic solution. Glucose infusion rates of 10 to 15 mg/kg/minute may berequired to achieve stable serum glucose levels.

Hypokalemia – Hypokalemia may be caused by dilution from volume overload, ascites, or renal wasting.

Hypophosphatemia – Serum phosphorus should be monitored frequently, as hypophosphatemia can beprofound. While the mechanism is unknown, hypophosphatemia is presumed to result from increased needsdue to active liver cell regeneration. Hyperphosphatemia, often associated with renal insufficiency, isconsidered a poor prognostic sign [11].

Acid­base disturbances – Acid­base disturbances are caused by a variety of mechanisms, includingrespiratory alkalosis from hyperventilation, respiratory acidosis from respiratory failure, metabolic alkalosisfrom hypokalemia, and metabolic acidosis from hepatic necrosis, shock, and increased anaerobic metabolismor as the result of inborn errors of metabolism.

Total fluid input including PN, blood products, and medications should generally be limited to between 85 to95 percent of the maintenance fluid requirement to avoid excessive hydration.

Protein input should generally be no more than 1 g/kg/day, but this may need to be reduced to 0.5 mg/kg/dayfor patients with elevated serum ammonia levels.

Trace metals (trace elements) should generally be eliminated or reduced. This is because copper andmanganese are metabolized in the liver. Moreover, chromium, molybdenum, and selenium should beeliminated or reduced if renal disease is also present.

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&searchT… 6/16

hepatic assist devices and hepatocyte transplantation'.)

Plasmapheresis or plasma exchange facilitates the removal of suspected toxins in the blood to facilitate a milieu inwhich the liver might recover or regenerate, but has not been helpful in the management of children or adults withacute liver failure (ALF). While coagulation profiles may improve, the procedure has not been shown to improveneurological outcome or ability of the liver to recover spontaneously. An exception is that for patients with ALF dueto Wilson disease, plasma exchange can be valuable because it rapidly removes large amounts of copper. (See"Wilson disease: Treatment and prognosis", section on 'Acute liver failure'.)

A number of specific interventions have been studied, but are unhelpful for ALF and should generally not be used.These include glucocorticoids (except in the setting of autoimmune hepatitis), hepatic “regeneration therapy” usinginsulin and glucagon, charcoal hemoperfusion, and prostaglandin E. Furthermore, a randomized, doubly masked,controlled trial in pediatric acute liver failure (PALF) demonstrated that intravenous N­acetylcysteine (NAC) was notbeneficial in children with non­acetaminophen­induced ALF [13]. One­year survival with native liver was significantlyworse for those receiving NAC than placebo, particularly for those children younger than two years of age. (See"Acute liver failure in adults: Management and prognosis", section on 'Unhelpful treatments'.)

DISEASE SEVERITY ASSESSMENT — There are currently no reliable tools to predict survival or death in patientswith pediatric acute liver failure (PALF). Biochemical tests (lactate, total bilirubin, phosphorous, internationalnormalization ratio [INR], prothrombin time, ammonia, Gc­globulin), clinical features (encephalopathy, cerebraledema), diagnosis (eg, acetaminophen), or combinations of the three have been tried without reliable success.

Existing liver failure scoring systems, including the Kings College Hospital Criteria (KCHC), the Clichy score, Modelfor End­Stage Liver Disease (MELD) score, and Pediatric End­Stage Liver Disease (PELD) score, are not adequateprognostic tools because they are only weakly associated with outcome [2]. Among these, only PELD is specificto the pediatric age group, but it was developed for chronic rather than acute liver disease, and includes factorssuch as growth failure that are less relevant to prognosis in acute liver failure (ALF). KCHC is commonly used topredict prognosis and need for liver transplantation in adults with ALF, and is stratified by whether the ALF iscaused by acetaminophen toxicity. However, KCHC are not useful in PALF [14]. (See "Acute liver failure in adults:Management and prognosis", section on 'King's College Criteria'.)

The Liver Injury Unit (LIU) score has been developed specifically for PALF and is somewhat more useful [15]. Itincludes factors for peak total bilirubin, prothrombin time (PT) or international normalization ratio (INR), andammonia. A study tested the validity of the LIU score using data from the Pediatric Acute Liver Failure Study Group(PALFSG), and after optimization sensitivity and specificity were 74 and 80 percent, respectively [16]. While thisrepresents an improvement compared with the other scoring systems mentioned above, LIU is not sufficient tomake critical decisions about liver transplantation. We believe the ideal scoring system should reflect the dynamicnature of PALF and incorporate periodic clinical changes into deriving the likelihood of death or survival [3].

LIVER TRANSPLANT

Liver transplant decisions — In the era before liver transplantation (LT) was available, the natural history ofpediatric acute liver failure (PALF) was for children to either survive or die. LT interrupts the natural course of PALF,and can save the life of a patient with acute liver failure (ALF) if he or she has a condition that is not amenable totreatment or fails to respond to treatment (figure 2). However, because the cause of PALF often is not known, andthe course of PALF is difficult to predict, it is likely that some patients may receive LT in situations in whichspontaneous recovery may have occurred.

LT decisions are difficult because of uncertainty regarding the patient’s outcome without transplant, the potentialmorbidity and mortality of the transplant procedure, and the limited number of organs available. Moreover, long­termoutcomes following LT for PALF are less favorable as compared with LT for chronic liver diseases such as biliaryatresia. This is likely due to multiple factors, including the severity of illness at the time of LT, and the possibilitythat LT was performed in circumstances in which death was inevitable regardless of LT. When living donor LT isconsidered, the decision also includes consideration of potential risks to the donor.

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&searchT… 7/16

As discussed above, none of the current scoring systems are adequate to direct decisions about LT for patientswith PALF. A more reliable modeling scheme is needed to readily and effectively distinguish the patient who woulddie from the one who would survive without LT and recognize when it would be futile to proceed with LT. Until then,the best solution is a global clinical assessment by a team of clinicians with experience in PALF and LT,incorporating the prognosis associated with the cause of the ALF, and the patient’s dynamic course, based onrepeated assessments of the probability of survival with native liver from one time interval to the next.

LT decisions are particularly challenging for patients with PALF caused by a mitochondrial disease. Multisystemmitochondrial dysfunction is a contraindication to liver transplantation [17]. However, patients who do not haveextrahepatic manifestations of disease may have isolated hepatic mitochondrial dysfunction and could becandidates for liver transplantation [18]. Unfortunately, multisystem involvement may not be apparent at the time ofLT, placing the child at risk for developing symptoms in the future. Moreover, patients whose ALF was triggered byvalproate have a very poor prognosis after LT, due to a high likelihood of mitochondrial disease (especially POLGmutations), and extrahepatic disease progression [17,19,20]. (See "Acute liver failure in children: Etiology andevaluation", section on 'Older infants and young children'.)

Organ allocation in acute liver failure — Organ allocation for children with ALF remains an evolving process.Organ allocation in the United States is managed by United Network for Organ Sharing (UNOS), and is basedlargely on disease severity scores for adults (Model for End­Stage Liver Disease [MELD]) and children (PediatricEnd Stage Liver Disease [PELD]) to support organ allocation for patients with chronic liver disease. PELD iscalculated by UNOS or by using a calculator (calculator 1). MELD is used for patients 12 years and older and isdiscussed in detail separately. (See "Model for End­stage Liver Disease (MELD)".)

PELD and MELD are used to allocate organs for patients with chronic liver disease; they were not designed for usein ALF. The urgency of liver transplantation for PALF is typically not reflected by their PELD/MELD score. Patientswith ALF and in need of liver transplantation are given priority over those listed with a PELD/MELD score and arelisted as Status 1A, the category with the highest priority status. Status 1A is reserved for children in an intensivecare unit (ICU) in one of four diagnostic categories, including fulminant liver failure. The three other diagnosticcategories qualifying for Status 1A are primary graft nonfunction following liver transplantation, hepatic arterythrombosis, and acute decompensated Wilson disease.

To qualify for Status 1A for fulminant liver failure, UNOS uses the following criteria:

Children who are classified as Status 1A require reassessment of their listing status after seven days. At any time,the child can be removed from the transplantation list if he/she becomes too ill to undergo transplantation orrecovers to a point that transplantation is not necessary. If the child is still on the list after seven days, optionswould be to continue to list the patient as Status 1A by providing supportive clinical information, remove the childfrom the list, or “demote” the urgency by changing the listing status from Status 1A to the calculated PELD score.

Types of grafts — LT has improved overall survival for children with ALF. Because the supply of appropriately sizedorgans from deceased donors is inadequate, some children with PALF die while waiting for LT, and pretransplantmortality is worse than for patients with chronic liver failure. As a result, technical variants to whole grafts such assplit and living donors have been introduced.

In a report of LT for PALF from centers in the United States and Canada, deceased­donor whole livers were used in

Onset of hepatic encephalopathy within eight weeks of the first symptoms of liver disease in the absence ofpreexisting liver disease, AND one of the following:

Ventilator dependence•

Need for dialysis, continuous venovenous hemofiltration, or continuous venovenous hemodialysis•

INR >2.0•

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&searchT… 8/16

46 percent of transplants, split or cut­down grafts were used in 38 percent, and grafts from living donors were usedin 14 percent [21]. Outcomes for patients receiving donor or split liver grafts were not different from those receivingwhole liver grafts. However, in a separate study that focused on patients with ALF and concurrent multiorgan failure,living donor transplant was associated with improved 30­day and 6­month survival compared with recipients of adeceased donor liver allograft [22]. Improved outcome for patients receiving a living donor LT is likely related to areduced cold ischemia time and wait time, resulting in a more expeditious time to transplant for these seriously illchildren.

Auxiliary liver transplantation is an alternative approach that consists of placement of a graft adjacent to thepatient's native liver (auxiliary heterotopic liver transplantation) or in the hepatic bed after a portion of the native liver(auxiliary orthotopic liver transplantation) has been removed. This technique has been used as a “bridge” to provideneed time for the native liver to regenerate, but challenges remain as to the timing for withdrawal ofimmunosuppression and involution of the transplanted graft [23]. (See "Acute liver failure in adults: Managementand prognosis", section on 'Auxiliary liver transplantation'.)

Hepatocyte transplant — The role of hepatocyte transplantation in PALF is yet to be determined and may be anopportunity for investigation in the future [17,24]. Hepatocyte transplantation may serve as a bridge to transplant or,perhaps, a “cure” for some children with metabolic diseases. It has been used in a small number of children withALF. However, technical challenges as well as lack of a readily available source for hepatocytes have limited theopportunity for this procedure at most centers. (See "Hepatocyte transplantation".)

OUTCOMES — In the pretransplant era and using an adult definition of acute liver failure (ALF), spontaneoussurvival occurred in 28 percent of patients overall, and only 4 percent of those with stage IV coma [25]. Morerecently, with improvements in management of critically ill children, coupled with a more lenient definition ofpediatric acute liver failure (PALF), outcomes have improved [1­3,26]. However, it should be noted that all currentstudies of outcomes are affected by decisions about liver transplantation (LT), because LT interrupts the naturalcourse of PALF. Some children who receive LT may have recovered spontaneously, and some die as aconsequence of LT rather than of the underlying PALF. Patient outcome depends on a number of factors includingthe etiology, disease severity, supportive management, and treatment. However, outcomes vary among childrenwith seemingly similar etiology, disease severity, and treatment. Additional factors are likely involved to explainthese variations perhaps including the inflammatory milieu, end­organ damage, immune activation, and potential forliver regeneration.

Data from the Pediatric Acute Liver Failure Study Group (PALFSG) in North America and Europe revealed that 21­day outcome varied by diagnosis, age, and degree of encephalopathy [1,26]. Spontaneous survival (survival with thenative liver) was highest amongst those with liver failure due to acetaminophen (94 percent). Spontaneous survivaloccurred less frequently for those with liver failure due to metabolic disease (44 percent), for those with non­acetaminophen drug­induced disease (41 percent), and for those with an indeterminate diagnosis (45 percent). Asmight be expected, those with higher stages of encephalopathy had lower spontaneous survival.

Unexpectedly, in the same study, 21 percent of patients with minimal or no clinical evidence of encephalopathy (ie,those with peak hepatic encephalopathy stage 0) either died or received a LT [1]. For children with an establisheddiagnosis, between 20 to 33 percent received a LT; and of those with acetaminophen­induced PALF, only 2 percentreceived a LT. In comparison, among patients with a diagnosis of indeterminant PALF, 46 percent underwent LT.Therefore, children who do not have a specific diagnosis are more likely to receive a LT. The major causes of deathfor children with PALF who do not receive a liver transplant are multiorgan system failure, cerebral edema andherniation, and sepsis.

Both early and late graft loss and death is higher among children who undergo LT for ALF than for those withchronic liver disease [27]. Reasons for these findings are uncertain, but one possibility includes immunedysregulation that may be associated with PALF, which could lead to increased susceptibility to infection or graftrejection. Among patients undergoing LT for PALF, overall survival rates are 74 percent at one year, and 69 percentat four years [21].

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&searchT… 9/16

SUMMARY AND RECOMMENDATIONS — Pediatric acute liver failure (PALF) is a complex, rapidly progressiveclinical syndrome that precipitates complications and failure in most other organ systems. Treatment of PALFrequires management of each of these complications, supportive care, and informed decisions about livertransplantation.

Patients with PALF typically should initially be managed in a pediatric intensive care unit, which allows closemonitoring, particularly fluid status and changes in mental status. (See 'Clinical setting' above.)

Laboratory monitoring should include a complete blood count, electrolytes, renal function tests, glucose,calcium, phosphorous, ammonia, coagulation profile, total and direct bilirubin, and blood cultures. (See'Laboratory monitoring' above.)

Fluid intake should be modestly restricted for most patients with PALF. In the absence of the need for volumeresuscitation, total intravenous fluids should initially be restricted to between 85 to 95 percent of themaintenance fluid requirement. (See 'Fluids' above.)

Hepatic encephalopathy (HE) develops in the majority of patients with PALF and is a relevant but inconsistentindicator of prognosis. Serial clinical evaluations of behavior, cognition, neurological examination, andelectroencephalogram (EEG) are important to assess the presence and progress of HE and possible onset ofcerebral edema. We suggest that patients with HE be treated initially with lactulose, although the evidence tosupport this approach is weak (Grade 2C). (See 'Encephalopathy' above.)

Management of cerebral edema requires meticulous supportive care, sometimes guided by surgicalplacement of an intracranial pressure monitor. (See 'Cerebral edema' above.)

The prothrombin time (PT) and international normalization ratio (INR) are used to assess the severity of liverinjury in the setting of PALF because these tests reflect hepatic production of clotting factors. However, thePT/INR is not a good marker for the risk of bleeding in patients with PALF, because PALF reduces bothprocoagulant proteins and anticoagulant proteins. Therefore, we suggest NOT administering with plasma orother procoagulation products except in patients with active bleeding or in anticipation of an invasive surgicalprocedure (Grade 2C). (See 'Coagulopathy' above.)

Hepatorenal syndrome (HRS) is a feared renal complication associated with PALF. Unlike prerenal azotemia,the urine sodium typically is low, and there is no improvement with volume expansion. Renal replacementtherapy with hemofiltration or dialysis may be necessary in some cases, but only liver transplantation (LT) canreverse HRS. (See 'Renal' above.)

Metabolic disturbances often seen in patients with PALF include hypoglycemia, hypokalemiahypophosphatemia, and acid­base disturbances. Management requires close monitoring and replacement.Hypoglycemia may require a continuous infusion of hypertonic glucose solution via a central venous catheter.(See 'Metabolic' above.)

Patients with PALF are susceptible to bacterial infection and sepsis because of immune system dysfunction.Evidence of infection may be subtle, and fever may not be present. Thus, blood cultures should be obtainedwith any evidence of clinical deterioration, and antibiotics should be initiated if there is a clinical concern forsepsis. (See 'Infectious' above.)

Decisions about whether and when to perform a LT for a patient with PALF are difficult because of uncertaintyregarding the patient’s outcome without LT and the potential morbidity and mortality of the LT procedure. Noneof the current scoring systems are adequate to direct decisions about LT. (See 'Disease severity assessment'above and 'Liver transplant decisions' above.)

Outcomes for patients with PALF vary substantially by diagnosis; acetaminophen­related PALF typically hasthe highest likelihood of survival without LT (94 percent) as compared with non­acetaminophen drug­inducedPALF (41 percent) or indeterminant PALF (45 percent). Other important prognostic factors include age, timing

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&search… 10/16

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Squires RH Jr, Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first 348 patients in thepediatric acute liver failure study group. J Pediatr 2006; 148:652.

2. Squires RH Jr. Acute liver failure in children. Semin Liver Dis 2008; 28:153.3. Squires RH, Alonso EM. Acute liver failure in children. In: Liver Disease in Children, 4th ed, Suchy FJ, Sokol

RJ, Balistreri WF (Eds), Cambridge University Press, New York 2012.4. Whittington PF, Alonso AE. Fulminant hepatitis and acute liver failure. In: Diseases of the liver and biliary

system in children, 2nd ed, Kelly DA (Ed), Blackwell, Oxford 2003. p.107.5. Debray D, Yousef N, Durand P. New management options for end­stage chronic liver disease and acute liver

failure: potential for pediatric patients. Paediatr Drugs 2006; 8:1.6. Wendon J, Lee W. Encephalopathy and cerebral edema in the setting of acute liver failure: pathogenesis and

management. Neurocrit Care 2008; 9:97.7. Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver failure: recommendations of

the U.S. Acute Liver Failure Study Group. Crit Care Med 2007; 35:2498.8. Kamat P, Kunde S, Vos M, et al. Invasive intracranial pressure monitoring is a useful adjunct in the

management of severe hepatic encephalopathy associated with pediatric acute liver failure. Pediatr Crit CareMed 2012; 13:e33.

9. Shawcross DL, Wendon JA. The neurological manifestations of acute liver failure. Neurochem Int 2012;60:662.

10. Hadzić N, Height S, Ball S, et al. Evolution in the management of acute liver failure­associated aplasticanaemia in children: a single centre experience. J Hepatol 2008; 48:68.

11. Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen­inducedhepatotoxicity. Hepatology 2002; 36:659.

12. Rolando N, Harvey F, Brahm J, et al. Prospective study of bacterial infection in acute liver failure: an analysisof fifty patients. Hepatology 1990; 11:49.

13. Squires RH, Dhawan A, Alonso E, et al. Intravenous N­acetylcysteine in pediatric patients withnonacetaminophen acute liver failure: a placebo­controlled clinical trial. Hepatology 2013; 57:1542.

14. Sundaram V, Shneider BL, Dhawan A, et al. King's College Hospital Criteria for non­acetaminophen inducedacute liver failure in an international cohort of children. J Pediatr 2013; 162:319.

15. Liu E, MacKenzie T, Dobyns EL, et al. Characterization of acute liver failure and development of a continuousrisk of death staging system in children. J Hepatol 2006; 44:134.

16. Lu B, Zhang S, Narkewicz M, et al. Validation of a scoring system to predict survival in 455 patients withpediatric acute liver failure. Hepatology 2009; 50(4 Suppl):424A.

17. Squires RH, Ng V, Romero R, et al. Evaluation of the pediatric patient for liver transplantation: 2014 practiceguideline by the American Association for the Study of Liver Diseases, American Society of Transplantationand the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology 2014;60:362.

18. Sokal EM, Sokol R, Cormier V, et al. Liver transplantation in mitochondrial respiratory chain disorders. Eur JPediatr 1999; 158 Suppl 2:S81.

19. Stewart JD, Horvath R, Baruffini E, et al. Polymerase γ gene POLG determines the risk of sodium valproate­induced liver toxicity. Hepatology 2010; 52:1791.

20. Lee WS, Sokol RJ. Mitochondrial hepatopathies: advances in genetics, therapeutic approaches, and

of diagnosis for treatable disorders, and degree of encephalopathy (although a significant minority of patientswithout encephalopathy die or require LT).

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&search… 11/16

outcomes. J Pediatr 2013; 163:942.21. Baliga P, Alvarez S, Lindblad A, et al. Posttransplant survival in pediatric fulminant hepatic failure: the SPLIT

experience. Liver Transpl 2004; 10:1364.22. Mack CL, Ferrario M, Abecassis M, et al. Living donor liver transplantation for children with liver failure and

concurrent multiple organ system failure. Liver Transpl 2001; 7:890.23. Girlanda R, Vilca­Melendez H, Srinivasan P, et al. Immunosuppression withdrawal after auxiliary liver

transplantation for acute liver failure. Transplant Proc 2005; 37:1720.24. Soltys KA, Soto­Gutiérrez A, Nagaya M, et al. Barriers to the successful treatment of liver disease by

hepatocyte transplantation. J Hepatol 2010; 53:769.25. Psacharopoulos HT, Mowat AP, Davies M, et al. Fulminant hepatic failure in childhood: an analysis of 31

cases. Arch Dis Child 1980; 55:252.26. Sundaram SS, Alonso EM, Narkewicz MR, et al. Characterization and outcomes of young infants with acute

liver failure. J Pediatr 2011; 159:813.27. Soltys KA, Mazariegos GV, Squires RH, et al. Late graft loss or death in pediatric liver transplantation: an

analysis of the SPLIT database. Am J Transplant 2007; 7:2165.

Topic 83172 Version 6.0

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&search… 12/16

GRAPHICS

Stages of hepatic encephalopathy in infants and children from birth to48 months of age

Stage Clinical ReflexesNeurological

signs

Noencephalopathy(stage 0)

Normal Normal None

Early (stage I and II)

Inconsolable crying, sleep reversal,inattention to task, child is not actinglike self to parents

Unreliable/normal orhyperreflexic

Untestable

Mid (stage III)

Somnolence, stupor, combativeness Unreliable/hyperreflexic

Likelyuntestable

Late (stage IV)

Comatose, arouses with painful stimuli(stage IVa) or no response (stage IVb)

Absent Decerebrate ordecorticate

Modified with permission from: Squires RH, Alonso EM. Acute liver failure in children. In: Liver Disease inChildren, 4th ed, Suchy FJ, Sokol RJ, Balistreri WF (Eds), Cambridge University Press, New York 2012.Copyright © 2012 Cambridge University Press.

Graphic 83748 Version 2.0

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&search… 13/16

Grading system for hepatic encephalopathy

Grade Mental status Asterixis EEG

I Euphoria/depression Yes/no Usually normal

Mild confusion

Slurred speech

Disordered sleep

II Lethargy Yes Abnormal

Moderate confusion

III Marked confusion Yes Abnormal

Incoherent

Sleeping but arousable

IV Coma No Abnormal

Graphic 62922 Version 1.0

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&search… 14/16

Clinical features of hepatic encephalopathy

Diagram depicting the grade of hepatic encephalopathy and the clinical featuresassociated with advancing stages.

Data from: Conn HO, Lieberthal MM. The hepatic coma syndromes and lactulose. LippincottWilliams & Wilkins, Baltimore 1979.

Graphic 70740 Version 3.0

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&search… 15/16

Schematic model of the natural course and outcome of acuteliver failure in children

SIRS: systemic inflammatory response syndrome.

Reproduced with permission from: Squires RH, Alonso EM. Acute liver failure in children. In:Liver Disease in Children, 4th ed, Suchy FJ, Sokol RJ, Balistreri WF (Eds), Cambridge UniversityPress, New York 2012. Copyright © 2012 Cambridge University Press.

Graphic 83763 Version 1.0

4/4/2015 Acute liver failure in children: Management

http://www.uptodate.com/contents/acute­liver­failure­in­children­management?topicKey=PEDS%2F83172&elapsedTimeMs=0&source=search_result&search… 16/16

Disclosures: Robert H Squires, Jr, MD, FAAP Nothing to disclose. Elizabeth B Rand, MD Nothing to disclose. Alison G Hoppin, MDNothing to disclose.Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi­level review process, and through requirements for references to be provided to support the content. Appropriately referencedcontent is required of all authors and must conform to UpToDate standards of evidence.Conflict of interest policy

Disclosures