Medical Management of Acute

Liver Failure 9
Heli Bhatt and Girish S. Rao

Introduction and Definition liver injury in a child with no known evidence of

chronic liver disease and:
Acute liver failure (ALF) is among the very few
dramatically devastating illnesses in medicine. It (a) Prothrombin time (PT) ≥15 s or international
is a rare disorder characterized by rapid-onset normalized ratio (INR) ≥1.5 not corrected by
severe hepatocellular injury and dysfunction vitamin K administration in presence of
which can quickly progress to multisystem organ hepatic encephalopathy (HE)
failure and death. It is characterized by signs of (b) PT ≥20 s or INR ≥1.5 not corrected by vita-
severe liver function abnormalities including min K administration irrespective of the
jaundice, coagulopathy, and/or hepatic encepha- presence or absence of hepatic encephalopa-
lopathy within a few weeks of onset of the dis- thy [3]
ease. In adults, ALF is defined as onset of hepatic
encephalopathy within 8 weeks of signs of hepatic The exact incidence of PALF is unknown;
dysfunction, i.e., jaundice and coagulopathy [1]. however, PALF accounts for about 10–15% of
This definition of ALF in adults cannot be applied pediatric liver transplants performed in the USA
directly to children because it is difficult to accu- annually [6]. A specific diagnosis is not available
rately assess age-appropriate mental status and for almost half of these patients [3]. The data for
exact duration of illness in children. Also, hepatic outcome of this devastating illness is limited. The
encephalopathy may not be clinically apparent recent data regarding patient outcome from the
until terminal stages of liver failure in children PALF study group demonstrated that age less
[2]. This makes diagnosis of acute liver failure than 3 years, indeterminate or non-acetamino-
especially challenging in children [3, 4]. phen-induced liver failure, higher grades of
The Pediatric Acute Liver Failure (PALF) encephalopathy, bilirubin ≥5 mg/dL, and INR
study group is a multisite, multinational consor- ≥2.55 on admission are all associated with worse
tium established in 1999 to prospectively study outcomes [3].
ALF in children [3, 5]. This study group defines
PALF as biochemical/laboratory evidence of
Etiology
H. Bhatt · G. S. Rao (*)
Riley Hospital for Children at Indiana University The etiology of ALF in children varies between
Health, Division of Pediatric Gastroenterology, infants versus older children [7]. The most com-
Hepatology, and Nutrition, Indianapolis, IN, USA mon overall cause of PALF is indeterminate.
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 155

C. W. Mastropietro, K. M. Valentine (eds.), Pediatric Critical Care,
https://doi.org/10.1007/978-3-319-96499-7_9
156 H. Bhatt and G. S. Rao

Up to 40–50% patients with PALF lack a spe- including electrolytes, blood urea nitrogen
cific etiological diagnosis partly due to lack of (BUN), creatinine (Cr), and albumin, liver
thorough diagnostic evaluation [8]. In infants, enzymes, total and fractionated bilirubin,
infections and metabolic diseases are the most gamma-glutamyl transferase (GGT), coagula-
common known etiologies for PALF [7, 8]. tion profile along with prothrombin time (PT)
Herpes simplex virus is the most commonly with international normalized ratio (INR), a
identified infectious etiology in these children. complete blood count with differential and
Galactosemia, tyrosinemia, and fatty acid oxida- platelets, and a reliable serum ammonia level
tion defect are the commonly identified meta- should be obtained in all the patients at diagno-
bolic disorders in this age group, while neonatal sis and thereafter monitored closely. Additional
hemochromatosis was the most common cause tests to assess for etiology of liver failure should
of liver failure in the neonatal period [7]. In chil- be tailored to the age and presentation of the ill-
dren older than 7 months of age with ALF, drug ness. These should be targeted to evaluate for
toxicity, especially with acetaminophen over- infectious, metabolic, and autoimmune liver
dose, and autoimmune hepatitis are the most diseases in addition to drug or other toxin expo-
commonly identified etiologies [7, 8]. In devel- sures (Table 9.1) [9]. A complete abdominal
oping countries, infectious etiologies remain the ultrasound with Doppler should be obtained in
most common identified cause of acute liver fail- all patients with PALF, but additional imaging
ure through all age groups. Hepatitis A viral studies like CT, MRI, and/or MRCP should be
infection is the most common infectious agent in considered based on the individual case. Liver
these countries [8]. biopsy should be considered early in the course
of PALF to assess for the cause of liver failure
and the extent and pattern of hepatocyte injury.
Diagnostic Evaluation Transjugular approach is preferred in the setting
of severe coagulopathy with liver failure. The
All children with ALF should undergo thorough level of necrosis might be underestimated on
systematic evaluation for the underlying etiol- liver biopsy [10]. Submassive or massive liver
ogy of acute liver failure along with the assess- necrosis is associated with poor prognosis [11].
ment for liver injury, dysfunction, and
multisystem complications. This diagnostic
evaluation should be individualized and directed Management
toward the age-specific causes of acute liver fail-
ure. A detailed medical history including onset Management of acute liver failure is very chal-
of symptoms and neurological changes; history lenging due to multiple reasons. The multisystem
of exposure to infections or medications; family organ involvement with potential for rapid dete-
medical history including history of liver dis- rioration and death in absence of timely liver
ease, consanguinity, genetic, metabolic, or auto- transplant makes this disease one of the most dif-
immune diseases; and/or sibling death should be ficult diseases to manage. At the same time, there
obtained in all patients with acute liver failure. A is a tremendous potential for self-recovery with-
thorough physical examination with special out transplant and unnecessary morbidity can be
attention to mentation and neurological status is avoided by preventing transplants in these cases.
imperative. There is a lack of adequate data on management
Radiological and laboratory tests in PALF of PALF due to its rarity and currently, the major-
should be obtained to evaluate underlying etiol- ity of our clinical practice guidance is derived
ogy, to assess the extent of liver injury and fail- from adult studies. Hence, many principles of
ure, or to monitor for potential complications of management of this disease are currently unclear
liver failure. A comprehensive metabolic panel and controversial.
9 Medical Management of Acute Liver Failure 157

Table 9.1 Diagnostic evaluation [85]

Age-based causes Diagnostic evaluation
Idiopathic or indeterminate (all ages) Liver function tests: AST, ALT, GGT, alkaline
phosphatase, fractionated bilirubin, albumin, total protein
Coagulation: PT-INR, aPTT, fibrinogen, factors V, VII,
VIII
Ammonia level, blood gas, CBC with PLT, and
differential
Complete metabolic panel: electrolytes, BUN, creatinine,
blood glucose, Ca, Mg, P
Imaging studies: ultrasound liver with Doppler study
Tissue diagnosis: liver biopsy; muscle biopsy as indicated
Infectious:
1. Infancy: HSV 1 and 2 – most common, enterovirus, Viral PCR for EBV, CMV, enterovirus, adenovirus,
adenovirus, hepatitis B, hepatitis C, EBV, CMV, HHV-6, HSV 1 and 2, parvovirus
HHV 6, parvovirus Viral hepatitis serology including anti-HAV Ig M,
2. Preadolescence: hepatitis A, B, C, D, E, non-A and HBsAg, anti-HBe Ig M and Ig G, anti-HCV, and
non-B viral hepatitis, EBV, CMV, enterovirus, anti-HEV
adenovirus, HHV-6, parvovirus
3. Adolescents: hepatitis A, B, C, D, E, non-A and
non-B viral hepatitis, EBV, CMV
Metabolic:
1. Infancy: fatty acid defects, mitochondrial defects, Serum lactate, pyruvate, amino acid profile, carnitine
galactosemia, tyrosinemia, etc. profile, acyl-carnitine profile
2. Preadolescence: Wilson’s disease, fatty acid Urine amino acid/organic acid profile, urine
oxidation defects, mitochondrial defects, etc. succinylacetone, serum ceruloplasmin, and 24-h urine
3. Adolescents: Wilson’s disease, etc. copper
Immune dysregulation:
1. Infancy: neonatal hemochromatosis Ferritin, iron, TIBC
2. Preadolescence/adolescence: autoimmune hepatitis, Antinuclear antibody, anti-smooth muscle antibody,
HLH anti-liver-kidney-microsome antibody, Ig G level,
anti-soluble liver antigen/anti-liver pancreas antibody,
anti-liver cytosol type I antigen
Drug toxicity or accidental ingestion:
1. Infancy: acetaminophen, acetylsalicylic acid, Serum acetaminophen level, urine toxicology screen
valproic acid, etc.
2. Adolescence: acetaminophen, tetracycline, ecstasy,
toxic mushroom Amanita phalloides poisoning, etc.
HSV herpes simplex virus, EBV Epstein-Barr virus, CMV cytomegalovirus, HHV-6 human herpesvirus 6, AST aspartate
aminotransferase, ALT alanine aminotransferase, GGT gamma-glutamyl transferase, PT-INR prothrombin time and
international normalized ratio, aPTT activated partial thromboplastin time, PCR polymerase chain reaction, HAV hepa-
titis A virus, HBsAg hepatitis B surface antigen, HCV hepatitis C Virus, HEV hepatitis E virus, TIBC total iron-binding
capacity, HLH hemophagocytic lymphohistiocytosis

General Principles of Management significantly toward decreasing mortality in adult

ALF patients [12]. We can safely assume that
Pediatric patients with acute liver failure are best similar advances in pediatric critical care will
managed in intensive care units (ICU) by a mul- definitely improve outcomes in PALF.
tidisciplinary medical team. Intensive care units Patients with PALF demonstrating signs of
play a pivotal role by close monitoring and sup- altered mental status and/or worsening coagu-
porting of failing organs as well as providing lopathy should be closely monitored in the
clinical stability for multiple lifesaving interven- ICU with frequent neurological and cardiore-
tions. Advances in critical care have contributed spiratory assessments. After initial
158 H. Bhatt and G. S. Rao

c­ haracterization of ­presentation and stabiliza- Close collaboration between pediatric inten-

tion of the patient, further management should sivist, pediatric hepatologist, transplant surgeons,
be focused on monitoring and supporting the neurologist, nephrologist, and metabolic/genetic
patient and organ systems, identifying and disease specialist is crucial to provide the best
treating complications (Table 9.2), employing outcome for the patient. Early transfer to a trans-
targeted diagnostic evaluation, and optimizing plant center should be of utmost importance to
outcomes [5]. facilitate the multidisciplinary approach and

Table 9.2 Management of complications in PALF [85]

Organ system Complications Management of complications
Central nervous Hepatic encephalopathy Supportive care in ICU, minimal stimulation
system Cerebral edema Endotracheal intubation for grade 3 or 4
Intracranial hypertension encephalopathy
Consider CT/MRI head for any acute mental status
changes
Prophylactic HTS (3–30%) or mannitol 0.25–1.0
gm/kg IV bolus, repeated once or twice
Cardiovascular Systemic hypotension due to Adequate fluid resuscitation with IV crystalloids
intravascular volume depletion Norepinephrine for volume-refractory hypotension
Hyperdynamic circulatory failure Consider vasopressin and its analogs
Adrenal Relative adrenal insufficiency (RAI) Consider a trial of systemic steroids in patients with
Hepatoadrenal syndrome persistent vasopressor, fluid refractory shock
Respiratory Acute respiratory failure Endotracheal intubation for respiratory failure or
Pulmonary edema airway protection in advanced stages of hepatic
Pulmonary hemorrhage encephalopathy
Acute respiratory distress syndrome Ventilator strategies: low tidal volumes (5–8 ml/kg
(ARDS) of predicted weight) and moderately elevated PEEP
levels; avoid sustained hyperventilation
Renal Acute kidney injury (AKI) Preventive measures: maintain fluid balance,
Hepatorenal syndrome minimize nephrotoxic medications or IV contrast
CRRT is preferred
Fluid, electrolytes, Hypoglycemia Continuous glucose infusion to maintain
and nutrition Hyperammonemia euglycemia
Intravascular volume depletion Consider CRRT
Alkalosis and acidosis Frequent monitoring and correction of electrolytes
Electrolyte abnormalities and acid-base balance
Catabolic state with negative nitrogen Avoid hyponatremia to prevent cerebral edema
balance and increased energy Enteral nutrition with high caloric density formula
expenditure to avoid excess free water
Parenteral nutrition: a safe second-line choice in
patients who cannot be fed enterally
Hematological Coagulopathy not corrected by Plasma or platelet transfusions only recommended
vitamin K administration prior to invasive procedure or during active
Disseminated intravascular bleeding
coagulopathy Vitamin K administration is recommended
Gastrointestinal Gastrointestinal bleeding H2 blocker or proton pump inhibitors for
Ascites prophylaxis of gastrointestinal bleed
Spironolactone for diuresis in patients with ascites
who have respiratory compromise or discomfort
Infectious Systemic inflammatory response Aggressive surveillance with cultures and empiric
syndrome antibiotics in the presence of SIRS, worsening
Bacterial infections such as encephalopathy, refractory hypotension
staphylococci, streptococci, and No role for prophylactic antimicrobials
enteric gram-negative bacteria
HTS hypertonic saline, CRRT continuous renal replacement therapy, SIRS systemic inflammatory response syndrome
9 Medical Management of Acute Liver Failure 159

timely decision-making for critical aspects of olism that is generated from the breakdown of
patient care and interventions including trans- glutamine by glutaminase, an enzyme within the
plantation and its evaluation. enterocytes of the small intestine and colon, and
by urease-producing bacteria that inhabit the gut.
This gut-derived ammonia enters the urea cycle
Central Nervous System to be detoxified into urea and excreted in the
urine. Ammonia that bypasses this detoxification
Hepatic encephalopathy (HE) is a neuropsychiat- is converted to glutamine in hepatocytes, skeletal
ric syndrome associated with liver failure in the myocytes, and astrocytes in brain. Astrocytes are
absence of a preexisting brain disease. It is char- the most abundant type of cells in the brain. They
acterized by progressive but reversible deteriora- are very sensitive to a rapid increase in ammonia,
tion of behavior, cognition, and mentation in which subsequently leads to cellular edema due
patients with PALF. The clinical features of to increased influx of water secondary to osmotic
hepatic encephalopathy can range from overt gradient created by increased intracellular gluta-
coma to irritability to minor changes in behavior mine. Although hyperammonemia has been
and motor or cognitive skills. In children, fea- implicated to play a pivotal role in development
tures of HE can be subtle and difficult to assess of hepatic encephalopathy, a consistent correla-
and range from mild irritability to inactivity to tion between the plasma concentration of ammo-
coma. Table 9.3 describes the clinical stages of nia and clinical manifestation of HE has not been
encephalopathy originally developed to assess established [14]. In addition to hyperammone-
patients with cirrhosis but is used in ALF for the mia, increased proinflammatory circulatory cyto-
lack of a better clinical tool. In the Pediatric kines like IL-1β, IL-6, and TNF-α can modulate
Acute Liver Failure study group database, the cerebral blood flow and cellular permeability to
majority of the patients (75%) had grade 1–2 have direct or permissive effects on development
hepatic encephalopathy, and grade 3 and 4 and progression of HE into cerebral edema [15].
encephalopathy were seen in 17% and 7%
patients, respectively. Out of 348 patients
included in this study group, more than half Management of Hepatic
developed hepatic encephalopathy [3]. Encephalopathy
The exact pathogenesis of hepatic encepha-
lopathy is complex, is not completely understood, Given the potential for rapid neurological deteri-
and involves a number of interrelated factors [4, oration in patients with PALF and HE, early rec-
13]. Ammonia is a by-product of nitrogen metab- ognition and prompt management of HE are

Table 9.3 Stage of encephalopathy [4, 5]

Grade Symptoms Signs Reflexes EEG
Grade Normal None Normal Normal
0
Grade Inconsolable crying, Difficult to Difficult to examine; normal Difficult to obtain
1 confused, not acting like self examine or hyperreflexic if able to
examine
Grade Inconsolable crying, Difficult to Normal or hyperreflexic Difficult to obtain
2 drowsiness, not acting like examine
self
Grade Combativeness, increasing Rigidity Hyperreflexic, positive Generalized
3 somnolence, stupor Babinski sign slowing
Grade Comatose, may or may not Decerebrate or Absent Abnormal, very
4 arouse with painful stimuli decorticate slow, delta activity
posturing
160 H. Bhatt and G. S. Rao

necessary to decrease morbidity and mortality in Currently, there is no data to support their use in
these patients. As mentioned above, these patients PALF. The benefit of continuous renal replace-
should be closely monitored in a critical care set- ment therapy (CRRT) in reducing serum ammo-
ting with frequent neurological assessments. nia and improving 21-day transplant-free survival
There should be minimal stimulation, and unnec- has been demonstrated in a recent cohort study
essary interventions should be avoided. from US ALF study group registry [21].
Endotracheal intubation for airway protection or
controlled ventilation in advanced stages of
encephalopathy should be considered. Head of Management of Intracranial
the bed should be elevated to 20–30°, and the Hypertension and Cerebral Edema
patient’s head should be maintained in the mid-
line to provide optimal CSF drainage and jugular The goal in the management of cerebral edema
venous outflow. Aggressive efforts to maintain and intracranial hypertension is maintaining ade-
normothermia are crucial as fever and shivering quate cerebral perfusion pressure (CPP) while
may exacerbate intracranial pressure (ICP). lowering and maintaining intracranial pressure
Ventilation, oxygenation, and mean arterial pres- (ICP) to less than 20 mm Hg to assure adequate
sures should be meticulously monitored and perfusion of the brain [4, 22]. Close clinical mon-
maintained. itoring is strongly recommended but highly chal-
Lactulose and nonabsorbable oral antibiotics lenging in pediatric patients, especially if they
like neomycin and rifaximin have been used for have progressed to grade 3–4 HE. Cushing’s triad
prophylaxis and management of HE in patients of irregular breathing, systemic hypertension,
with chronic liver disease and cirrhosis. Lactulose and bradycardia is not uniformly present.
is a synthetic nonabsorbable disaccharide which Intracranial pressure monitoring can be used to
can be used to decrease intraluminal pH in the assess CPP to avoid hypoxic brain injury.
colon and prevent uptake of ammonia from the Multiple studies have been done to evaluate the
gastrointestinal lumen. Given the central role of safety and efficacy of invasive intracranial pres-
increased arterial ammonia levels in the patho- sure monitoring in management of ALF, but there
genesis of hepatic encephalopathy, one could has been no demonstrated improvement in sur-
assume that ammonia-lowering strategies might vival [23–25]. The use of invasive intracranial
be effective in halting the progression of neuro- monitoring in PALF is controversial owing to the
logical deterioration. While the abovementioned lack of sufficient evidence for its routine use and
agents have a role in preventing progression of safety. Maintaining systemic blood pressure by
HE associated with cirrhosis in patients with adequate volume resuscitation and use of vasoac-
chronic liver disease, there are no controlled tri- tive medications as well as aggressively treating
als to support the use of these medications to treat fluid overload with CRRT are crucial to maintain
hepatic encephalopathy in ALF [16–18]. In one adequate CPP.
nonrandomized retrospective series, there was no The principal therapy to reduce cerebral
improvement in outcome with lactulose therapy edema and increased intracranial pressure is
[19]. Lactulose use should be avoided in PALF as administration of osmotic agents like hypertonic
it has the potential to cause intravascular volume saline and mannitol [26]. Mannitol is a hyperos-
depletion, hypernatremia, and bowel distension molar agent, which works by promoting move-
or megacolon, which can be dangerous during ment of water from astrocytes into the serum by
transplant [16, 17]. Neomycin is also not recom- increasing osmolality of serum. Mannitol also
mended due to increased risk of nephrotoxicity decreases viscosity of blood causing vasocon-
[16]. L-Ornithine L-aspartate (LOLA) and striction, which leads to less cerebral blood vol-
L-ornithine phenyl acetate (LOPA) have shown ume and decreased ICP. It is used as a first-line
promising results in adult trials [20]. These work agent in management of increased ICP in adults
by increasing renal excretion of ammonia. with ALF [16, 17]. The recommended dose for
9 Medical Management of Acute Liver Failure 161

use is 0.25–1.0 gm/kg IV bolus that can be acute life-threatening mannitol-refractory wors-
repeated once or twice [16, 17]. The majority of ening of intracranial pressure to delay impending
information on mannitol in PALF is extrapolated cerebral herniation, but sustained hyperventila-
from adult literature. The effect of mannitol is tion should be avoided in patients with ALF.
transient, and it is difficult to achieve sustained Hypothermia prevents cerebral edema by
reduction of ICP to acceptable levels with man- decreasing cerebral metabolism, neuronal inflam-
nitol alone. The use of mannitol is not recom- mation, and oxidative stress. It also decreases
mended in presence of renal failure, hypovolemia, ammonia level and improves cerebral hemody-
or serum osmolality >320 mOsm/L [16, 17]. namics. Therapeutic hypothermia to 32–35° has
Hypertonic saline (3–30%) decreases ICP by been used in adults with ALF to reduce ICP for
mechanisms similar to mannitol. In addition, it successfully bridging these patients to liver trans-
also stabilizes cerebral endothelial cell volume plantation. There have been a few reports of ben-
and improves cerebral circulation. In a random- eficial effects of therapeutic hypothermia in adult
ized controlled trial from King’s College, patients patients with ALF [31, 32]. However, there have
who received hypertonic saline had decreased been complications reported with therapeutic
ICP from baseline in the first 24 h, and the inci- hypothermia too. These include cardiac dys-
dence of ICP >25 mm Hg or greater was signifi- rhythmias, increased risk of infection, coagulop-
cantly lower than control group; however, it did athy, electrolyte disturbances, hyperglycemia,
not show improved survival in patients treated and theoretical decreased hepatic regeneration
with HTS [27]. The use of hypertonic saline in [31, 32]. A multicenter retrospective cohort anal-
treatment of elevated ICP in PALF has not been ysis of 97 patients enrolled in the US ALF study
studied. In patients with PALF who have elevated group did not find a difference in 21-day mortal-
ICP, it is reasonable to maintain serum sodium ity as well as transplant-free survival with or
level around 145–150 mmol/L, especially now without the use of therapeutic hypothermia [33].
that hypertonic saline has been established as a There is no data to support the use of therapeutic
standard of care in management of pediatric hypothermia for neuroprotection. However,
patients with traumatic brain injury [28]. There hyperthermia should be aggressively managed to
are no randomized clinical trials regarding the avoid worsening of ICP. Currently, active normo-
use of hypertonic saline or mannitol in children. thermia (36–37°) remains the standard of care as
Hypertonic saline provides all benefits of hyper- it offers the best risk-benefit ratio [4].
osmolar agent without the hemodynamic side Early identification of neurological decline
effects associated with mannitol. According to and timely therapeutic interventions to minimize
2012 guidelines for the medical management of neurological morbidity are crucial in ALF
severe traumatic brain injury in children, use of because neurological morbidity is a major deter-
hypertonic saline is favored over the use of man- minant of outcome in ALF [4]. However, clinical
nitol for management of ICH [29]. assessment of neurological status in pediatric
Patients with ALF hyperventilate due to the patients can be difficult. Head imaging with com-
metabolic milieu associated with ALF, and this, puterized tomography (CT) scan is used to
in turn, helps restore cerebral autoregulation, exclude intracranial hemorrhage as a cause of
vasoconstriction, and reduction of ICP. Effects of sudden decline in neurological status. However,
hyperventilation are temporary and continuous in a recent single-center retrospective pediatric
hyperventilation offers no survival benefit in study assessing the role EEG in management of
patients with ALF [30]. Moreover, it has the PALF by Hussain et al. [34], CT and magnetic
potential to worsen cerebral edema due to cere- resonance imaging (MRI), even though abnormal
bral hypoperfusion. According to American in 13% of patients, failed to demonstrate consis-
Association for the Study of Liver Disease tent abnormalities to suggest the presence of
(AASLD) position paper for management of cerebral edema. There was no association
ALF, hyperventilation may be used to manage between EEG and CT/MRI findings in this study.
162 H. Bhatt and G. S. Rao

However, there was increased mortality in cially deleterious in advanced stages of hepatic
patients with certain EEG abnormalities. These encephalopathy. Pain management and sedation
included moderate to severe slowing, epilepti- are important components of critical care man-
form discharge, and electrographic seizure. EEG agement of children with ALF. Sedating non-
seems to be a very sensitive tool to screen not intubated patients may be necessary, and
only for subclinical seizures but also declining anxiolytics should be used after carefully weigh-
neurological status in patients progressing to ing the benefit of reducing agitation versus blunt-
grade 3 or 4 encephalopathy or with unexplained ing the signs of neurological deterioration and
clinical deterioration [34, 35]. Transcranial exacerbating encephalopathy [4]. Also, numer-
Doppler ultrasonography has been shown to be ous drugs used for sedation and analgesia have
helpful in measuring dynamic changes in ICP in hepatic or renal clearance. There is a lack of suf-
a small retrospective study in adults with ALF ficient data for the use of standard sedative or
[36]. There are no studies for this diagnostic analgesic agents in PALF. Short-acting agents,
modality in PALF. with appropriate dose adjustments for liver dys-
Seizure activity worsens cerebral edema by function, should be used. Benzodiazepines can
increasing the oxygen requirement of the astro- have prolonged sedative effect when used in
cytes [35]. The true frequency of seizures in patients with hepatic impairment and should be
patients with ALF may be underestimated with- avoided. Furthermore, benzodiazepines and pro-
out continuous EEG. In the study by Hussain pofol have the potential to worsen HE by increas-
et al. 11% of patients had clinical seizures; how- ing gamma-aminobutyric acid (GABA)
ever, almost 5% of patients had subclinical non- neurotransmission [38]. Propofol in limited doses
convulsive seizures [34]. Continuous EEG should and for short period of time may be used in older
be used in patients with grade 3 or 4 HE or with children without mitochondrial disease, due to
acute decline in neurological status to rule out shorter recovery time and neuroprotective effect
subclinical seizures [4, 35]. Aggressive antiepi- through decreased cerebral blood flow and
leptic therapy should be implemented to control decrease in ICP [4, 39]. Opioid agents with short
seizures to prevent further neurological morbid- half-life such as fentanyl and remifentanil can be
ity. Phenytoin can be used for prompt control of used concurrently to improve cardiovascular sta-
epileptiform activity, and short-acting benzodiaz- bility [16]. Dose adjustments are recommended
epines can be used in phenytoin-refractory cases while using dexmedetomidine for its sedative and
[17]. Valproic acid should be avoided if mito- analgesic effect in PALF as it is metabolized pri-
chondrial disease is suspected as the underlying marily in the liver [40]. Atracurium and cisatra-
etiology for ALF. Prophylactic phenytoin has curium are the preferred agents for neuromuscular
been tried to suppress subclinical epileptiform blockade in PALF. These undergo ester hydroly-
activity in adults with ALF; however, a subse- sis and Hoffman elimination, and their duration
quent trial demonstrated no benefit of its use in of action in liver failure is similar to the same in
preventing seizures, brain edema, or improving normal liver function [41]. Vecuronium and
survival [35, 37]. There are no pediatric trials to rocuronium should be avoided in ALF as they
support the use of prophylactic phenytoin in undergo hepatic metabolism.
management of PALF. Prophylactic phenytoin,
therefore, cannot be recommended in PALF at
this time. Although there are rare reports of drug- Cardiovascular
induced liver injury with levetiracetam, it can be
safely used in management of seizures in PALF. Hyperdynamic circulatory failure with low mean
Pain can arise from multiple diagnostic and arterial pressure occurs in ALF due to peripheral
therapeutic interventions and procedures in vasodilation caused by elevated circulatory cyto-
patients with PALF. Psychomotor agitation is kines. This significantly decreases peripheral tis-
known to increase ICP, and this may be espe- sue oxygenation exacerbating multi-organ
9 Medical Management of Acute Liver Failure 163

failure. Depleted intravascular volume due to pressor/fluid refractory hypotension may benefit
decreased intake as well as increased transuda- from a trial of systemic corticosteroid adminis-
tion into extravascular space adds to this hemo- tration [16, 45, 46].
dynamic instability.
As with any patient with hypotension, intra-
vascular volume status should be assessed and Respiratory
replenished with adequate volume replacement
[17]. If the patient remains hypotensive after fluid In adults, about 20–30% patients with ALF are
resuscitation, vasopressors should be initiated to diagnosed with acute respiratory distress syn-
maintain mean arterial pressures within the age- drome (ARDS) [47]. Exact incidence of ARDS in
appropriate normal range. This is crucial to PALF is unknown. According to the PALF study
assure adequate cerebral perfusion pressure. group data, almost 40% children with PALF
Norepinephrine has been the preferred agent in required ventilator support [3]. Endotracheal
adults, mainly, because it provides a more consis- intubation may be required in PALF either for
tent and predictable increase in cerebral perfu- airway protection in patients with hepatic
sion while minimizing tachycardia and preserving encephalopathy or for management of respiratory
splanchnic circulation [16]. Despite the lack of failure secondary to sepsis, fluid overload-associ-
adequate pediatric data on choice of vasopres- ated pulmonary edema, pulmonary hemorrhage,
sors, norepinephrine does seem to be a reason- or ARDS.
able choice to optimize organ perfusion in PALF There are no pediatric trials directing mechan-
[4]. Vasopressin and its analogues can be used in ical ventilation in children with PALF. Mechanical
volume- and norepinephrine-refractory cases to ventilation strategies in PALF should aim at
potentiate its effects; however, these should be decreasing ventilator associated lung injury while
used cautiously due to the potential direct cere- providing maximum neuroprotection in the set-
bral vasodilatory effect that may worsen intracra- ting of elevated intracranial pressure.
nial hypertension [16, 17]. Echocardiography can Conservative tidal volume ventilation (5–8 ml/kg
be used to assess for systolic and diastolic dys- of predicted body weight) with moderately ele-
function in patients not responding to volume and vated positive end expiratory pressures should be
vasoactive support. titrated to maintain normocapnia and avoid
hypoxemia [48]. As mentioned above, sustained
hyperventilation should be avoided as the effects
Adrenal of hyperventilation on intracranial pressure are
temporary, and there is a potential risk of worsen-
Although there is a discrepancy in the definition, ing cerebral edema by causing cerebral hypoxia
relative adrenal insufficiency/hepatoadrenal syn- [17]; however, it may be used briefly in sudden
drome has been well described in septic shock as life-threatening worsening of intracranial pres-
well as ALF [42]. A third of adults with ALF may sure that is refractory to osmotic agents to delay
develop relative adrenal insufficiency, and its impending cerebral herniation.
incidence seems to be directly proportional to the
severity of liver failure [43]. Low HDL levels
with increased circulatory endotoxins and proin- Renal
flammatory markers like TNF-α lead to impaired
cortisol secretion and impaired adrenal function Acute kidney injury (AKI), and subsequent renal
that can depress sensitivity to catecholamines failure, is a relatively common complication of
[43, 44]. No data is available to define this condi- ALF. In large retrospective review using patients
tion in PALF or to guide diagnosis and manage- in the US Acute Liver Failure study group
ment of relative adrenal insufficiency in (ALFSG), AKI was seen in almost 47% patients
PALF. However, children with PALF and vaso- with ALF [49]. In this study, there was decreased
164 H. Bhatt and G. S. Rao

overall survival in patients with AKI versus cient data. RRT (hemofiltration or dialysis) can
patients without AKI. Also, there was decreased help correct electrolyte imbalances, worsening
transplant-free survival in patients needing renal acidosis, fluid overload, and hyperammonemia.
replacement therapy (RRT) or with advanced The degree of kidney injury, electrolyte distur-
AKI versus those without AKI [49]. Although bance, and fluid imbalance should be integrated
exact incidence of AKI in PALF is unknown, the into the decision to start RRT in patients with
prospective PALF study reported the need for PALF [4]. Continuous renal replacement therapy
hemofiltration in nearly 10% of patients [3]. AKI is preferred over intermittent hemodialysis due to
has been reported in 15–20% of children with lower risk of hemodynamic instability and wors-
ALF where it was associated with decreased sur- ening ICP [17, 55]. In a recent study on a large
vival [50]. cohort of patients enrolled in ALFSG, serum
AKI in ALF can be multifactorial, and causes ammonia modulation with CRRT improved
include hypovolemia, sepsis, acute tubular necro- 21-day transplant-free survival [21]. Although
sis, nephrotoxic medications, acetaminophen- there is inadequate data in PALF regarding use of
induced renal injury, and functional renal failure CRRT in management of HE, early use of CRRT
[51, 52]. Functional renal failure can arise from a should be considered in patients at a greater risk
mechanism similar to hepatorenal syndrome in of progression of HE (e.g., high-grade encepha-
chronic liver disease. Intrarenal vasoconstriction lopathy, advanced AKI, vasopressors, etc.).
leads to decreased renal perfusion and subse- AKI in PALF resolves after restoration of liver
quent kidney injury [51–53]. function in majority of cases. However, in certain
Assessment of renal dysfunction in chil- circumstances, simultaneous liver and kidney
dren with ALF may be augmented by using transplantation must be considered. In adults,
multiple criteria such as the combination of indications for concurrent liver/kidney transplan-
serum creatinine (sCr), urinary output, and tations are based on degree and duration of renal
fluid balance aid in diagnosing AKI. SCr by injury and are strongly considered if patient has
itself may overestimate renal function, and needed dialysis for 8–12 weeks [57]. However,
change of SCr over baseline is more relevant there is minimal data, mainly based on single-
over a single value to assess progression of center experience, available for guidance regard-
renal injury [54, 55]. Urinary biomarkers like ing liver/kidney transplant in children [58].
neutrophil gelatinase-associated lipocalin,
IL-18, kidney injury molecule-1, and liver-
type fatty acid-binding protein are emerging Fluid, Electrolytes, and Nutrition
for evaluation of pediatric AKI; however, these
have not been studied in PALF [56]. Acid-base imbalances, electrolyte abnormalities,
Management of AKI in PALF should be and metabolic derangements are common in
focused on interventions to reduce kidney injury PALF and need to be identified and corrected fas-
and prevent progression to renal failure. Adequate tidiously due to their life-threatening potential.
hydration, avoiding excessive diuresis, maintain- Serum electrolytes should be monitored fre-
ing adequate renal perfusion pressure, and mini- quently and corrected meticulously to prevent
mizing the use or adjusting the dose of intravenous mortality and decrease morbidity in these criti-
contrast and nephrotoxic medications are some cally ill patients. Alkalosis and acidosis both may
measures to prevent AKI in ALF [16, 17, 52]. occur in ALF and should be managed by correct-
Intravenous fluid challenge should be considered ing the cause of acid-base imbalance [17].
in patients with suspected prerenal azotemia, but Hyponatremia and hypokalemia can be second-
volume overload should be avoided in patients ary to ascites, dilution from aggressive volume
with PALF [4]. resuscitation, and urinary losses from diuretic
The criteria for initiation or discontinuation of use. Hyponatremia should be strictly avoided as
RRT in PALF are ill-defined due to lack of suffi- it can exacerbate cerebral edema.
9 Medical Management of Acute Liver Failure 165

Hypophosphatemia, hypocalcemia, and [62]. Overall incidence of bleeding was about

­hypomagnesemia are commonly observed, can 10% with spontaneous upper gastrointestinal
be profound, and should be corrected. bleed being the most common location in
ALF is a catabolic state with negative nitrogen ALF. Although elevated INR with or without
balance due to decreased oral intake and increased encephalopathy is a universal requirement for
energy expenditure. Caloric requirements in diagnosing a patient with ALF, INR is not a good
these patients increase by about 20% [59]. There predictor of risk of bleeding. Elevation in INR is
is some data to guide nutrition in children with due to decrease in both pro- and anticoagulant
chronic liver disease and cirrhosis which can be factors, and it reflects the synthetic dysfunction
extrapolated to PALF in the absence of studies to of the liver more precisely than the risk of bleed-
guide nutritional support in PALF [59]. Nutrition ing in ALF. In the abovementioned study, a low
in PALF should be aimed at providing adequate platelet count, severity of systemic complica-
calories to meet the metabolic needs, enough glu- tions, and SIRS were found to be more important
cose to maintain euglycemia, and appropriate risk factors for bleeding than INR [62]. Platelet
amounts of protein to overcome negative nitro- count as well as some less commonly used coag-
gen balance without worsening hyperammone- ulation tests like thromboelastography may be
mia [60]. In general, enteral feeds should be used better in assessing the severity of bleeding dia-
when possible. Formula with high caloric density thesis [63, 64] as well as guiding potential
should be preferred to avoid excess free water interventions.
administration [16]. Parenteral nutrition is safe in Administration of vitamin K is recommended
PALF and can be used as a second-line option to as vitamin K deficiency has been reported in
provide adequate nutrition in patients who cannot adults with ALF [65]. Prophylactic administra-
tolerate enteral feedings [60]. When using paren- tion of plasma to correct INR may be deleterious
teral nutrition, intravenous lipids can be used as a not only due to associated adverse effects of vol-
source of nutrition; however, they should be ume overload, transfusion-related lung injury,
avoided in patients with some disorders such as and immune dysregulation but also due to its
mitochondrial diseases due to the concern for potential to exacerbate a preexisting hypercoagu-
abnormal fat metabolism [61]. Glucose infusion lable state leading to microvascular thrombosis
rates as high as 10–15 mg/kg/min may be worsening the primary hepatic injury [62].
required to maintain euglycemia in patients with However, plasma transfusion can be used prior to
ALF [4]. Children with ALF have dysregulated invasive procedures or in the setting of active
homeostatic responses to hypoglycemia, and bleeding [17]. In patients with ALF at risk of vol-
signs of hypoglycemia may be obscured in the ume overload due to renal injury, recombinant
patients with HE. Even though tight glycemic factor VIIa (rFVIIa) can be used to facilitate inva-
control is promoted for critically ill patients in sive procedures; however, these must be used
certain ICUs across the nation, a significant risk with caution as systemic venous thrombosis has
can be created with such aggressive interventions been reported with its use [66, 67]. Platelet trans-
in children with PALF and should be avoided [4, fusions are advised if platelets <10,000 or
16, 17]. <50,000 with evidence of overt bleeding or need
for invasive procedure. However, platelet transfu-
sion is not recommended for platelet count
Hematology-Coagulopathy >50,000 [16, 17].

In a recent study on 1770 adults with ALF

enrolled in ALFSG, spontaneous or post-proce- Gastrointestinal
dural bleeding was deemed as a proximate cause
of death in less than 5% of patients, half of whom Clinically significant bleeding is rare despite the
had bled after the placement of an ICP monitor degree of elevation of INR [68]. Gastrointestinal
166 H. Bhatt and G. S. Rao

bleeding in patients with ALF is mainly stress no clear guidelines for the use of prophylactic
induced or acid related. The AASLD guidelines on antibiotics or antifungals for liver failure in
management of ALF recommend H2 blockers or adults or children, and these should be avoided
proton pump inhibitors (PPI) for prophylactic pre- [16, 17]. Pulmonary, urinary, and blood stream
vention of this type of GI bleeding [17]. Variceal infections are the most common sites for bacte-
bleeding is rare in patients with ALF. Ascites may rial infection, and gram-positive cocci like
develop in a minority of patients with ALF, and staphylococci and streptococci and enteric gram-
spironolactone is the drug of choice to manage negative bacilli are the most commonly isolated
ascites of hepatic origin. Diuresis is indicated only organisms [66]. Obtaining appropriate evalua-
if there is respiratory compromise or significant tions in patients with ALF and signs/symptoms
discomfort due to abdominal distension. of infection should not be delayed. This may
Aggressive diuresis should be avoided to prevent include chest x-ray and urine and blood cultures
precipitation of hepatorenal syndrome [5]. with any suspicion of infection, SIRS, refractory
hypotension, or worsening encephalopathy [16,
17]. Empiric antibiotics should be initiated in
Infection: SIRS patients exhibiting SIRS and should have ade-
quate coverage for the abovementioned bacterial
The liver is involved in multiple immune-related infections.
functions which are disturbed in ALF making
these patients more susceptible to infection.
Additionally, these patients have defects in many Liver Support Systems
other host defense mechanism pathways which
decrease their ability to fight against infections. In acute liver failure, CRRT is highly effective in
As a result, infection and systemic inflammatory the removal of smaller molecules of water-solu-
response syndrome contribute to significant mor- ble toxins, i.e., urea, ammonia, etc. However, the
bidity and mortality in these patients. Bacterial larger or albumin-bound non-water-soluble mol-
infections account for 10–37% of mortality in ecules like cytokines, bile acids, bilirubin, and
adults with ALF [69, 70]. In a retrospective metabolites of aromatic amino acids and medium
review, the incidence of bacterial infection in chain fatty acids are not successfully removed
children with PALF was about 25%, and bacterial during hemodialysis. These large albumin-bound
infections were associated with increased mor- non-soluble molecules accumulate and contrib-
bidity in these patients [71]. Systemic inflamma- ute to progression of liver failure [73, 74]. High-
tory response syndrome (SIRS) has been reported volume hemofiltration has been used to remove
in 50–60% of adults with ALF [69]. Increased circulatory cytokines and was associated with
SIRS components are directly correlated to improved hemodynamics and encephalopathy
increasing mortality and are strongly associated [75]. In a randomized control trial in adults with
with worsening encephalopathy. Encephalopathy ALF, high-volume nonselective plasmapheresis
has been shown to progress in majority of patients demonstrated improved transplant-free survival
with infection and in 50% of patients with greater when compared to a control group along with
than two SIRS components versus 25% of decreased SIRS score and SOFA score [76].
patients without SIRS [72]. There are no retro- High-volume plasmapheresis dampened innate
spective or prospective studies to assess the asso- immune response, and early use of plasmapher-
ciation or incidence of infection or SIRS with esis might provide a window of homeostasis for
outcomes in PALF. the liver to regenerate [76]. However, a small ret-
In spite of several studies examining the use rospective pediatric study failed to show survival
of prophylactic antibiotics in management of benefit with the use of plasma exchange [77].
ALF, the results remain inconclusive. There are
9 Medical Management of Acute Liver Failure 167

Artificial Support Systems have demonstrated improvements in biochemi-

cal profile but have limited clinical and survival
Artificial and bioartificial systems have been benefits. Plasma exchange may improve sur-
devised to help detoxify the plasma or blood and vival; however, further studies are needed to jus-
support the patient either until the native liver tify its use in PALF. Based on lack of convincing
recovers or as a bridge to transplant. The artifi- survival benefit in adult studies and paucity of
cial support systems use series of filters to pro- data in PALF, liver support systems are not cur-
vide detoxification support. These sorbent-based rently advocated in children with liver failure
systems use adherent particles in an extracorpo- [82].
real circuit to help detoxify the blood from vari-
ous cytokines which indirectly help improve the
biochemical and clinical parameters in patients. Liver Transplantation
Molecular adsorbent recirculating system
(MARS) and Prometheus are the two commer- Liver transplantation is a lifesaving intervention
cially available liver support systems. These in patients who fail to show signs of spontane-
have been successfully used in adults with ALF ous recovery with supportive care and have oth-
to improve biochemical parameters like ammo- erwise guarded prognosis. Timely
nia as well as HE [78]. However, a recent RCT transplantation is critical to minimize posttrans-
failed to demonstrate any survival benefit with plant morbidity and improve survival in these
the use of MARS in patients with liver failure patients. About 10% of pediatric liver trans-
[79]. A recent pediatric case series on use of plants in the USA are performed on children
MARS in 20 patients with PALF reported sig- with PALF [6]. Uncontrolled sepsis, certain
nificant improvement in serum ammonia, biliru- mitochondrial disorders, and cerebral edema
bin, bile acids, and creatinine levels but without with uncal herniation are contraindications for
any survival benefit [80]. liver transplant, and the AASLD guidelines for
evaluation of a pediatric patient for liver trans-
plantation recommend identifying underlying
Bioartificial Support Systems etiology for PALF to recognize treatable etiolo-
gies (Table 9.4) as well as contraindications for
The bioartificial or biologic systems use cellular liver transplant [83].
material which, in theory, not only provide detoxi- Liver transplantation for ALF has been asso-
fication but have the potential to mimic synthetic ciated with inferior outcomes than liver trans-
functions of the hepatocytes. These types of sup- plantation for chronic liver diseases [84]. In the
port systems use hepatocytes, human or nonhu- SPLIT database, factors predicting worse out-
man in origin, with or without concurrent use of comes were age <1 year, advanced/grade 4 HE,
other sorbents. Five such systems are currently and need for dialysis prior to transplantation
being clinically tested. These include [84]. In a recent single-center outcome report on
HepatAssist™, extracorporeal liver support device 122 PALF patients who underwent liver trans-
(ELAD™), modular extracorporeal liver support plantation, 1-year, 5-year, and 10-year survival
system (MELS™), bioartificial liver support sys- rates were 81%, 77%, and 73%, respectively
tem (BLSS™), and Amsterdam Medical Center [85]. In the same study, low creatinine clearance
bioartificial liver (AMC-BAL™). A randomized and less than 7 days between onset or jaundice
control trial assessing the role of bioartificial liver and encephalopathy were associated with poor
support system did not demonstrate any benefit in patient survival. Age less than 2 years, low cre-
survival between treatment and control group [81]. atinine clearance, and PELD/MELD score
The limited studies evaluating the role of greater than 25 were associated with increased
artificial and bioartificial liver support systems graft loss [85].
168 H. Bhatt and G. S. Rao

Table 9.4 Etiology specific treatment [4, 5]

Etiology Diagnosis Treatment
Infections
Hepatitis B Hepatitis B PCR, hepatitis B surface or e Lamivudine, tenofovir, entecavir
antigen
HSV 1,2 Viral PCR, viral culture from vesicles, IV acyclovir
oropharynx, conjunctiva, blood, and CSF
Enterovirus Viral PCR Pleconaril – possibly helpful
Parvovirus Viral PCR IV immunoglobulin – possibly
helpful
Metabolic
Galactosemia Elevated urine non-glucose-reducing Switch to lactose-free formula
substances, galactose-1 phosphatase uridyl
transferase enzyme assay
Tyrosinemia type 1 Markedly elevated AFP, elevated urine PO NTBC
succinylacetone, enzyme assay or genetic
testing for fumarylacetoacetate hydrolase
Wilson’s disease Low serum ceruloplasmin, high 24-h urine Copper chelation with agents like
copper, high liver copper, presence of D-penicillamine, trientene, zinc,
Kayser-Fleischer rings (in approximately 50% etc.; sometimes plasmapheresis
patients) may be needed
Immune dysregulation
Autoimmune hepatitis Autoimmune hepatitis serology (see IV methylprednisolone while
Table 9.1); elevated Ig G levels concomitant evaluation for LT
Gestational alloimmune High serum ferritin; lip/salivary gland biopsy; High-dose IV immunoglobulin;
liver disease (GALD)/ characteristic features on MRI brain/liver/ can also be given prophylactic
neonatal hemochromatosis pancreas during pregnancy
May need exchange transfusion
Hemophagocytic Cytopenias, high serum triglyceride and High-dose corticosteroids,
lymphohistiocytosis (HLH) ferritin, low fibrinogen; high soluble IL-2 chemotherapy and/or bone
receptor, low or absent NK cell activity; marrow transplantation
genetic testing and/or bone marrow biopsy
proved to be diagnostic
Drugs/exposures
Acetaminophen History suggestive or suspicious of ingestion; NAC should be started as soon as
elevated acetaminophen level 4 h after possible in all patients where
ingestion acetaminophen overdose is
suspected.
Amanita toxicity History of Amanita phalloides and Amanita PO or IV silibinin
virosa ingestion
Others
Budd-Chiari syndrome Finding of hepatic vein thrombosis on imaging TIPS – if possible; LT might still
studies be necessary
AFP alpha-fetoprotein, LT liver transplantation, NTBC 2-(2-nitro-4-trifluoro-methyl-benzoyl)-1,3-cyclohexadion, IL
interleukin, NK cell natural killer cell

Prognosis (MELD) score, and the Sequential Organ Failure

Assessment (SOFA) score are among the few
There are several prognostic scoring systems most frequently used prognostic scoring systems
available; however, none of these have been able in adults. However, none of these adequately pre-
to well-define the indications for liver transplan- dict outcome or candidacy for transplantation,
tation. The King’s College Hospital Criteria and the AASLD guidelines for management of
(KCHC), the Model for End-Stage Liver Disease acute liver failure recommend against using these
9 Medical Management of Acute Liver Failure 169

for organ allocation [17]. Prognostic scoring sys- Conclusion

tems for PALF are poorly defined and not
­adequately validated. The KCHC has been exten- Despite the improvement in supportive care and
sively used in adult ALF; however, when the outcomes in PALF in last few decades, critical
PALF study group tried to validate the criteria for care management remains poorly defined and
use in non-acetaminophen-induced PALF guided mainly by adult data and guidelines. This
patients, it did not reliably predict chance of sur- makes PALF one of the most challenging condi-
vival in PALF, and its sensitivity and positive pre- tions to manage. Intense supportive care, thorough
dictive value were significantly lower than the diagnostic evaluation, and early detection with
original study [86]. Serum albumin level, serum prompt treatment of complications help improve
bilirubin level, PT-INR, age, and weight have outcomes. Improved availability of organs for
been used in the Pediatric End-Stage Liver transplant, better prognostic system, and effective
Disease (PELD) score to predict mortality in liver support systems are highly needed to improve
children with chronic liver disease [87]. This survival and decrease the uncertainty associated
scoring system has not been validated for use in with this devastating disease.
PALF. The pediatric liver injury unit (LIU) score
is an upcoming dynamic scoring system, which
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