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Indian J Pediatr (2010) 77:1288–1295

DOI 10.1007/s12098-010-0167-1

SYMPOSIUM ON PICU PROTOCOLS OF AIIMS

Intensive Care Management of Children with Acute


Liver Failure
Vidyut Bhatia & Rakesh Lodha

Received: 15 July 2010 / Accepted: 30 July 2010 / Published online: 27 August 2010
# Dr. K C Chaudhuri Foundation 2010

Abstract Acute liver failure is an uncommon condition The definition in adults of ALF as “evidence of coagulation
associated with multi organ involvement, high morbidity and abnormality, usually an INR ≥1.5, and any degree of mental
mortality. Etiology of acute liver failure varies with age and alteration (encephalopathy) in a patient without pre-existing
geographical location. Most cases of acute liver failure in India cirrhosis and with an illness of ≤26 weeks duration” [3] does
are due to infectious causes predominantly viral hepatitis. A not satisfactorily encompass the complexity of the condition
significant group with indeterminate causation remains, despite in the pediatric population. In the largest study of ALF in
careful investigation. The etiology of acute liver failure in children, the following definition of ALF was taken [4]:
infants is largely metabolic. The mainstay of management is
(1) Children with no known evidence of chronic liver
supportive care in an intensive care unit. Monitoring of clinical
disease,
and biochemical parameters is done frequently until the patient
(2) Biochemical evidence of acute liver injury, and
becomes stable. Mortality is predominantly due to raised
(3) hepatic-based coagulopathy defined as a prothrombin
intracranial pressure, infections and multi-organ failure. Liver
time (PT) ≥15 s or INR ≥1.5 not corrected by vitamin
transplant is an important life saving procedure for children
K in the presence of clinical hepatic encephalopathy
with acute liver failure.
(HE) or a PT ≥20 s or INR ≥2.0 regardless of the
presence or absence of clinical HE.
Keywords Acute liver failure . Viral hepatitis . Intensive
care management

Initial Assessment
Introduction
The history should include details about the onset of jaundice,
Acute liver failure is a rare but devastating illness with a very mental status changes, evidences of coagulation disturbances,
high mortality. Bucuvalas has defined liver failure as “....results vomiting, fever, contact with an infectious agent, blood
when loss of liver function, caused by rapid death or injury to transfusions and any relation to drug intake (acetaminophen,
a large proportion of hepatocytes, leaves insufficient paren- antituberculous treatment). Consanguinity in the family or
chymal mass to sustain life.”[1]. Liver failure can develop in history suggestive of Wilson’s disease, early infantile death,
absence of pre-existing liver disease when it is known simply viral hepatitis, autoimmune conditions should prompt a search
as acute liver failure (ALF) or as acute decompensation of a for the above conditions. The history should also be focused on
diseased liver secondary to a identified or unidentified liver ruling out any underlying chronic liver condition. Develop-
disorder known as acute on chronic liver failure (ACLF) [2]. mental delay or seizures suggest a metabolic condition.
Physical examination should include the assessment of
growth, development and nutrition of the child. Signs of
V. Bhatia : R. Lodha (*)
chronic liver disease like clubbing, telangiectasia, xanthomas,
Department of Pediatrics, All India Institute of Medical Sciences,
New Delhi 110029, India palmar erythema, and prominent abdominal veins should be
e-mail: rakesh_lodha@hotmail.com looked for. Fetor hepaticus, testicular atrophy and gynecomas-
Indian J Pediatr (2010) 77:1288–1295 1289

tia are rarely seen in children. The physical examination should 5. Daily coagulation studies and full blood counts
also include the liver span and its extent below the costal 6. Daily measurements of liver span and weight
margin, splenic enlargement, ascites and a complete neurolog- 7. Daily prescription review
ical examination for staging of the encephalopathy. 8. LFT, Urea, creatinine, calcium and phosphate twice-
After initial assessment of the child, the management weekly
progresses in multiple parallel paths (Fig. 1). The first path 9. Surveillance blood and urine cultures
consists of the immediate management of the patient. The
Consider mechanical ventilation of patients in grade-3 or
second concurrent path follows the etiological work-up of the
4 encephalopathy or with hypoxia [5]. If required, sedate
patient. The third path moves towards the management of
the child with midazolam. For painful or invasive proce-
complications.
dures, a short-acting sedative (like midazolam) along with
morphine/ fentanyl may be given. Otherwise, medications
that affect level of consciousness should be avoided in
Management
order not to complicate assessment of or worsen the
encephalopathy (Table 1).
ALF is a multisystem disease with a dynamic and often
unpredictable course. Mortality in ALF is predominantly due to
raised intracranial pressure, infections and multi-organ failure; Etiology
therefore, efforts are directed toward management of these
conditions while awaiting recovery of liver function or liver The etiology of acute liver failure varies with the age and
transplantation. Formulation of set protocols is restricted in the geographical location. Studies from India show that
view of scarcity of controlled clinical trials in pediatric infectious hepatitis is the most important cause of ALF in
populations. Most recommendations have been based on majority of the cases [6–11]. In the largest study on acute
observations from single-centre, uncontrolled trials or from liver failure in children, which included patients from
case series or extrapolated from adult studies. United States, England or Canada, the etiology in the 348
children included acute acetaminophen toxicity (14%),
Immediate Measures metabolic disease (10%), autoimmune liver disease (6%),
non-acetaminophen drug-related hepatotoxicity (5%), infec-
The child should be nursed in a quiet environment tions (6%), and other diagnosed conditions (10%); 49%
preferably in an intensive care setting. A central venous were indeterminate[4]. In infants, the main causes of ALF
line should be placed in order to measure central venous are inherited metabolic disorders and infections [12]
pressure, administer fluids, medications, and blood prod- (Table 2).
ucts, and collect blood samples. Volume resuscitation The initial investigations are directed towards establishing
should be carried out aggressively if required. Intravenous the etiology and performing a baseline evaluation of the
fluids should be started at 3/4th maintenance requirement. patient’s clinical status.
The fluids should be glucose based with a glucose infusion
rate of at least 6–8 mg/kg/min. The composition of Management of Complications
maintenance fluids can be tailored to the electrolyte, sugar
and renal status of the patient. Vasoactive drugs like Metabolic, Electrolyte and Acid Base Disturbances
dopamine, dobutamine, etc. should be used if clinically (Table 3)
indicated. Strict intake and output charting should be done.
Nasogastric tube should be inserted for feeding/ drainage Metabolic, electrolyte and acid-base disturbances frequently
and a urinary catheter for output measurement. Care of occur in acute liver failure. Most commonly seen are
bowel, back, bladder, skin, eyes should be done. hyponatremia, hypokalemia, hypocalcemia, hypophosphate-
Monitoring of clinical and biochemical parameters mia and hypomagnesemia.
should be done frequently until the patient becomes stable.
The following parameters should be monitored. Hyponatremia occurs commonly and is usually secondary
to decreased water excretion by the kidney, excess
1. Continuous oxygen saturation monitoring antidiuretic hormone or excess administration of hypotonic
2. 4 hourly vital signs (including blood pressure); more saline [13].
frequently in an unstable child
3. 12 hourly neurological observations/coma grading Hypernatremia can also occur secondary to vigorous use
4. 12 hourly electrolyte, sugar and arterial blood gases of lactulose [14].
1290 Indian J Pediatr (2010) 77:1288–1295

Fig. 1 Initial assessment and management of patients with deranged liver functions and mental status changes
Indian J Pediatr (2010) 77:1288–1295 1291

Table 1 Indian studies on children with acute liver failure following initial presentation [4]. Close monitoring in an
Year of Study Location n Contribution by Reference intensive care setting is recommended because the grade of
Infectious encephalopathy may change rapidly. With any sudden change
hepatitis
in mental status, the patient should be evaluated for
1996 AIIMS, New Delhi n=40 75% [6] hypoglycemia, infection, and intracranial hemorrhage. In
1999 Pune n=36 61.1% [7] patients who have grade 1–2 encephalopathy, sedatives should
2002 Chandigarh n=67 94% [8]
be avoided, and the patient should be observed closely in a
2004 SGRH, New Delhi n=32 62.5% [9]
2005 CMC, Vellore n=22 not clear [10]
quiet intensive care setting.
2007 Kolkata n=45 66.6% [11]

Management of Intracranial Hypertension (ICH)


(Table 5)
Hypokalemia Children with ALF usually have hypokalemia
but can present with hyperkalemia or normokalemia as well
In patients who have grade 3–4 encephalopathy, 70–80%
[15]. Serum levels of potassium can be normal even though
patients develop intracranial hypertension. It is also the most
total body potassium stores are reduced [16, 17]. The severity
common cause of death in them. The head should be elevated
of potassium depletion is related to the severity of liver
to 30° and endotracheal intubation should be performed (ensure
dysfunction. The postulated mechanisms are decreased dietary
adequate sedation during the procedure). During the elevation
intake, effects of chronic illness, increased losses in the urine
of the head of the bed, mean arterial pressure should be
due to diuretic therapy or secondary hyperaldosteronism and
maintained to avoid decreasing the cerebral perfusion pressure.
frequent gastrointestinal losses [15].
High levels of positive end-expiratory pressure (PEEP) should
Hypophosphatemia Severe hypophosphatemia is a common be avoided because they may increase hepatic venous pressure
occurrence in ALF patients. The severity of hypophosphatemia and intracranial pressure (ICP). Mannitol bolus of 0.5 g/kg as a
is postulated to be due to amount of regenerative liver mass. 20% solution over 15 min may be given in the event of acute
Phosphate levels return to normal as liver synthetic function rise of ICP. The boluses may be repeated provided that the
improves [18–20]. This is presumably because phosphate may serum osmolality is less than 320 mOsm/L. Other methods that
be a substrate for various kinase enzymes that phosphorylate are used include infusion of 3% hypertonic saline to keep serum
proteins that play critical role during rapid liver regeneration. sodium between 145–155 mEq/L [22]. Steroids are not
indicated for treatment of intracranial hypertension in ALF.
Acid base disturbances The origin of acid-base disorders in
patients with liver disease is complex [15]. As the liver’s
metabolic function worsens, particularly in the setting of renal Management of Coagulopathy and Hemorrhage
dysfunction, hemodynamic compromise, and hepatic enceph-
alopathy, acid-base disorders ensue. The most common acid- Intravenous vitamin K is given to correct any reversible
base disorder is respiratory alkalosis. Metabolic acidosis alone coagulopathy (2–10 mg). Correction of coagulopathy with
or in combination with respiratory alkalosis also is common.
All ALF patients should be started on maintenance I.V. fluids Table 2 Investigations in infants and children with acute liver failure
at admission with 3 mEq K+ (as 15% KCl) in every 100 ml of First Line investigations
fluid administered. After the serum K+ reports are available,
they should be given potassium supplements as per the Complete hemogram; Serum electrolytes; Blood Sugar; arterial blood gas
guidelines given in Table 3. Liver function tests; Kidney function tests; Cholesterol; Prothrombin time
Blood ammonia, lactate
Hypoglycemia Patients with acute liver failure are at increased Viral Markers: HBsAg; Anti HCV; HAV IgM; HEV IgM; HBc IgM
risk for hypoglycemia as a result of failure of hepatic Autoimmune markers: ANA/SMA/LKM
gluconeogenesis, hypoinsulinemia and secondary bacterial Ultrasound Abdomen
infections. Frequent monitoring of blood sugar, initially every Serum Ceruloplasmin; Eye examination (KF ring); 24 hrs urinary copper
excretion
1 to 2 h is recommended.
Special investigations for neonates and infants
Urinary succinylacetone
GALT assay
Management of Hepatic Encephalopathy (Table 4)
Alfa-fetoprotein
Serum ferritin
Two thirds of infants and children presenting with acute liver
Fructose challenge
failure develop hepatic encephalopathy during their first week
1292 Indian J Pediatr (2010) 77:1288–1295

Table 3 Fluid and metabolic complications and their management [21] Table 5 Management of intracranial hypertension

Abnormality Management Position Head end elevated and head in neutral position
Ventilation Elective; maintain pCO2 Between 25 to 28 mm Hg;
Hypotension • Resuscitate with normal saline, Ringer’s lactate, plasma this however, should be used only as a short term
or blood measure in view of the potential deleterious effect of
• Avoid fluid overload vasoconstriction on cerebral oxygen utilization.
• If shock does not improve with fluid administration, start Mannitol 0.5 g/kg as a 20% solution over 15 min. Monitor with
vasopressors; dopamine is the preferred initial drug serum osmolality
Metabolic • Suspect fluid deficit and correct Hypertonic 3% solution infusion (to maintain serum sodium between
acidosis • Look for sepsis saline 145–155 mEq/L)

Hypokalemia Give potassium chloride infusion (per 100 mL IV fluids) Corticosteroids Not indicated

• 3 mEq (1.5 mL KCl) if K+ >3 mEq/L


• 4 mEq (2 mL KCl) if K+ between 2.5 and 3 mEq/L and vasoconstrictors. The trigger for systemic vasoconstriction
• 5 mEq (2.5 mL KCl) if K between two and 2.5 mEq/L
+ is probably splanchnic vasodilatation that occurs following
• 6 mEq (3 mL KCl) if K+ below 2 mEq/L portal hypertension [24]. The International Ascites Club has
Metabolic • Increase potassium chloride to the next step classified HRS into two clinical types according to the rate of
Alkalosis progression of renal failure [25]. Type I HRS is characterized
Hyponatremia • Restrict fluids to 2/3 to 3/4 maintenance by rapidly progressive reduction of renal function as defined
• Restrict sodium infusion to less than 2 mEq/kg/day by a doubling of the initial serum creatinine to a level greater
Hypoglycemia • Increase the glucose infusion rate than 2.5 mg/dL or a 50% reduction of the initial 24-hour
• Maintain blood sugar between 100 to 200 mg/dL creatinine clearance to a level lower than 20 mL/min in less
than 2 weeks. The remaining types in which the renal failure
fresh frozen plasma is done only with hemorrhage or in does not have a rapidly progressive course are classified as
preparation for invasive procedures or if coagulopathy is type II HRS. This classification essentially meant for adults is
severe (PT >60 s). Usually 10 to 15 mL/kg of fresh frozen also being used in children as a separate classification system
plasma every six hours or an infusion of 3 to 5 mL/kg/hr is for children does not exist.
required. Platelet count and function are depressed in liver Therapy for HRS is primarily focussed on decreasing
failure and contribute to increased bleeding time. Throm- splanchnic circulation either with drugs (vasoconstrictors) or
bocytopenia should be corrected if the platelet count falls through TIPS procedure and maintaining circulating volume
below 50×109/L. with colloid or fresh frozen plasma. Studies in the adults have
used vasoconstrictor agents like vasopressin analogues (terli-
Prophylaxis for GI bleed The most common site of pressin) [26] and alpha agonists (norepinephrine and medo-
bleeding is the GI tract, hence prophylactic administration drine) and have shown them to be very effective in reversal of
of proton pump inhibitors (Pantoprazole- 20–40 mg/day in
children older than 5 years; Omeprazole 1 mg/kg/day) or Table 6 Recommended dietary intakes for children with acute and
acute on chronic liver failure
Ranitidine (3–5 mg/kg/day) is routinely done [23].
Component Recommended intake Comments Reference
Renal failure Functional renal failure or hepatorenal syndrome
Energy 150% of Children with long [30]
(HRS) is the most common cause of renal insufficiency in ALF. recommended standing liver disease
HRS is secondary to intense renal vasoconstriction which is in allowance already suffer from
turn due to activation of a number of systemic vasoconstrictor varying degrees of
malnutrition therefore
mechanisms and an imbalance between intra-renal vasodilators need extra calories
Carbohydrates 15–20 g/kg/day [31]
Table 4 Mangement of hepatic encephalopathy Fat 8 g/kg/day with 50% [31]
as medium chain
Bowel washes With acidic fluid (1 teaspoon vinegar in half liter triglycerides
of clean water), 6 to 8 hourly Protein (Non- 2–3 g/kg/day For promoting growth and [30]
Lactulose By oral or nasogastric route. 0.5 mL/kg/dose. Up encephalo- to maintain positive
to 4 times a day maximum 30 mL/dose. It pathic state) nitrogen balance.
should produce 2 to 4 loose acid stools per day Vegetable and dairy
product based.
Enteral feeding No restrictions in grade 1–2 encephalopathy; Protein Low grade (I-II) 1-2 Further protein restriction [30, 32]
vegetable proteins preferred (encepha- g/kg/day High grade can exacerbate HE by
Anticonvulsants (if Phenytoin or phenobarbitone lopathic (III-IV) 0.5–1 g/kg/ causing breakdown of
seizures present) state) day endogenous protein
Indian J Pediatr (2010) 77:1288–1295 1293

Table 7 Etiology specific management of underlying ALF Specific Management


Etiology Management Ref
Specific therapy should be administered if the underlying cause
Infections of ALF has been determined (Table 7).
Hepatitis B Lamivudine 4 mg/kg/day once daily orally [33]
HSV Acyclovir 10 mg/kg 8 hourly [34]
Drugs and Toxins
Liver Transplant
Acetaminophen NAC oral: 140 mg/kg loading dose followed by 17 [35]
Poisoning doses of 70 mg/kg every 4 hrs for a total of
1330 mg/kg over 72 hrs Liver transplant is an important life saving procedure for
NAC IV intermittent: 140 mg/kg loading dose followed
by 12 maintenance doses of 70 mg/kg every 4 hrs ALF in children [5]. It should be offered to those patients
NAC IV infusion: loading dose 150 mg/kg infused over whose condition is likely to be benefitted with transplan-
15 minutes, followed by 50 mg/kg infused over 4 hrs tation. Children should be listed for liver transplantation
and then 100 mg/kg infused over 16 hrs
Amanita Penicillin G 1 g/kg iv, silibinin 15–30 mg/kg/day and [36]
Table 8 Indications for liver transplant in children
Poisoning NAC as for acetaminophen poisoning
Immune Dysregulation
Chronic cholestatic liver disease
Autoimmune Methyl prednisolone 60 mg/kg IV [28,
hepatitis 37] Extrahepatic biliary atresia (most common indication)
Metabolic disorders Arteriohepatic dysplasia (Alagille syndrome)
Galactosemia Galactose and lactose free diets e.g. Nusobee, [38] Neonatal hepatitis
ProSoyal
Primary sclerosing cholangitis
HFI Fructose free diets, avoiding fructose and sorbitol [38]
infusions Caroli’s disease
Tyrosinemia Nitisinone, a diet low in phenylalanine and tyrosine [38– Langerhan’s cell histiocytosis (histiocytosis X)
41]
Inborn errors of metabolism
Bile acid synthesis Primary bile acid therapy [38]
defects Alpha-1-antitrypsin deficiency
Neonatal Anti-oxidant cocktail [42] Tyrosinemia
hemochro-
matosis Wilson’s disease
Miscellaneous metabolic or genetic liver disease
NAC N-acetyl cysteine Glycogen storage disease, type 1
Glycogen storage disease, type 4
Type 1 hyperoxaluria
functional renal insufficiency [24]. A suggested dosage Crigler-Najjar syndrome
regimen for drugs to be used in children with type 1 HRS is Ornithine transcarbamylase deficiency
as follows: Terlipressin: 5–20 μg/kg/dose every 4 h as IV Familial hypercholesterolemia
bolus and norepinephrine starting at 0.2 μg/kg/min, then Protein C deficiency

increased progressively so that blood pressure is maintained Niemann-Pick and other lipidosis
Gaucher’s disease
within normal for age [27].
Erythropoietic protoporphyria
Hemophilia A
Hemophilia B
Urea cycle enzyme deficiency
Feeding
Hepatocellular injury
Viral hepatitis
ALF is a catabolic state characterized by a negative nitrogen
Autoimmune hepatitis
balance and thus, with immunodeficiency [28]. Oral or
Drug-induced liver failure
nasogastric feeding is usually well tolerated and should be
Amanita mushroom poisoning
started as early as possible [29]. Enteral route of feeding is
Hepatic venous outflow tract obstruction
preferred because it is more physiologic and associated with
Mass occupying lesions
less risk of severe systemic infections. Initial scepticism
Hepatoblastoma
regarding increased risk of the variceal bleeding due to tube
Hepatocellular carcinoma
feeding has not been found to be supported by appropriate
Hemangioendothelioma
clinical trials. On the contrary, tube feeding yields superior
Miscellaneous
results over ad lib oral feeding. There is no role for dietary Cystic fibrosis
restrictions. Vegetable source of protein is preferred. The Congenital hepatic fibrosis
recommended nutritional intake in children with liver failure is TPN induced cirrhosis
given in Table 6.
1294 Indian J Pediatr (2010) 77:1288–1295

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