Acute liver failure medical therapy: Difference between revisions

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* [[Encephalopathy]]
* [[Encephalopathy]]


==Treatment of Complications==
====General measures====
 
* The management of acute liver failure involves taking care of the patient in an appropriate setting preferably a center with liver transplantation facility, monitoring and treating of complications and providing nutritional support.<ref name="pmid2933761">{{cite journal |vauthors=Khadzhidekova VB, Benova DK, Ivanov BA, Mileva MS, Kolev MI |title=[Mutagenic effect of the cytostatic drug thaliblastine on rat bone marrow cells when administered alone and in combination with radiation] |language=Russian |journal=Radiobiologiia |volume=25 |issue=5 |pages=656–60 |year=1985 |pmid=2933761 |doi= |url=}}</ref>
===General measures===
* The goal is to resuscitate the patient with adequate nutrition and optimization of [[fluid balance]].  
* Treatment always involves admission to hospital; often the [[intensive care unit]], or a close observation unit is required.
* Supportive treatment with adequate nutrition and optimization of [[fluid balance]] should be a main goal.
* [[Intubation]] and [[mechanical ventilation]] are indicated for stage 3 or 4 encephalopathy.
* [[Intubation]] and [[mechanical ventilation]] are indicated for stage 3 or 4 encephalopathy.
* Infections and [[sepsis]] are common occurrences with [[fulminant liver failure]]. Though prophylactic antibiotics decrease the risk of infection, it is not routinely recommended during acute liver failure, as no proven survival benefits from doing so. Nevertheless, broad coverage with antibiotics is recommended in suspected cases of sepsis.  
* Infections and [[sepsis]] are common occurrences with [[fulminant liver failure]]. Though prophylactic antibiotics decrease the risk of infection, it is not routinely recommended during acute liver failure, as no proven survival benefits from doing so. Nevertheless, broad coverage with antibiotics is recommended in suspected cases of sepsis.  
Line 25: Line 23:
* [[H2 receptor blocker]]s and [[proton pump inhibitors]] are indicated to prevent and treat [[stress gastropathy]].
* [[H2 receptor blocker]]s and [[proton pump inhibitors]] are indicated to prevent and treat [[stress gastropathy]].
* Early transfer to a liver transplantation center should be considered based on a patient's clinical status.
* Early transfer to a liver transplantation center should be considered based on a patient's clinical status.
===Management of Encephalopathy===
===Management of Encephalopathy===
* Grade I can be managed on the floors with adequate skilled nursing staff in a calm atmosphere, as it helps in reducing agitation.
* Grade I can be managed on the floors with adequate skilled nursing staff in a calm atmosphere, as it helps in reducing agitation.
* Grade II encephalopathy has must be managed in ICU setting.
* Grade II encephalopathy has must be managed in ICU setting.
* For grades III/IV encephalopathy, intubation and mechanical ventilation are required for management.
* For grades III/IV encephalopathy, intubation, and mechanical ventilation are required for management.
* Monitoring and management of hemodynamic and renal parameters as well as [[glucose]], [[electrolytes]] and acid/base status is also important.
* Monitoring and management of hemodynamic and renal parameters as well as [[glucose]], [[electrolytes]] and acid/base status is also important.



Revision as of 16:51, 24 November 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2]


Overview

Medical Therapy

The goal of medical therapies are to treat, correct, or prevent the following conditions:

General measures

  • The management of acute liver failure involves taking care of the patient in an appropriate setting preferably a center with liver transplantation facility, monitoring and treating of complications and providing nutritional support.[1]
  • The goal is to resuscitate the patient with adequate nutrition and optimization of fluid balance.
  • Intubation and mechanical ventilation are indicated for stage 3 or 4 encephalopathy.
  • Infections and sepsis are common occurrences with fulminant liver failure. Though prophylactic antibiotics decrease the risk of infection, it is not routinely recommended during acute liver failure, as no proven survival benefits from doing so. Nevertheless, broad coverage with antibiotics is recommended in suspected cases of sepsis.
  • Routine administration of steroids for adrenal insufficiency are not recommended.
  • H2 receptor blockers and proton pump inhibitors are indicated to prevent and treat stress gastropathy.
  • Early transfer to a liver transplantation center should be considered based on a patient's clinical status.

Management of Encephalopathy

  • Grade I can be managed on the floors with adequate skilled nursing staff in a calm atmosphere, as it helps in reducing agitation.
  • Grade II encephalopathy has must be managed in ICU setting.
  • For grades III/IV encephalopathy, intubation, and mechanical ventilation are required for management.
  • Monitoring and management of hemodynamic and renal parameters as well as glucose, electrolytes and acid/base status is also important.

Management of Increased Intracranial Pressure

  • Monitoring for increased intracranial pressure in severe encephalopathy, and impending cerebral edema should be done with extradural sensors
  • The goal should be to maintain the intracranial pressure below 20 mm Hg, and the cerebral perfusion pressure above 70 mm Hg.
  • Lactulose is indicated in cases of encephalopathy.
  • Mannitol, 0.5 g/kg, or 100–200 mL of a 20% solution by intravenous infusion over 10 minutes for is indicated for reducing cerebral edema.
  • Mannitol should be avoided in patients with advanced chronic kidney disease.
  • Hypernatremia (145-155 mEq/L) can be induced through intravenous hypertonic saline infusion to reduce intracranial hypertension.
  • Hypothermia (32–34 °C) may reduce intracranial pressure in refractory cases.
  • Other measures such as elevation of the head of the bed to 30 degrees, hyperventilation and intravenous prostaglandin E1 can also be used.
  • Short-acting barbiturates, propofol, or IV indomethacin can be used for refractory intracranial hypertension.

Management of Infection

  • The use of antimicrobials as a prophylaxis may reduce infections in a few patients with acute liver failure, but has no survival benefit.[2]
  • If prophylaxis is not started, there should be ongoing surveillance for the development of infections.
  • There is an association of SIRS (systemic inflammatory response syndrome) with infection, which may worsen prognosis.

Management of Coagulopathy and Bleeding Complications

  • Coagulopathy constitutes a part of the definition for acute liver failure.
  • If there is no evidence of bleeding and INR is not in the normal range, treating the INR with fluids such as plasma may lead to volume overload and may cause transfusion related lung injury.
  • Vitamin K should be administered routinely (5- 10 mg SC) as there is decreased synthesis of clotting factors from the liver tissue.
  • In high risk procedures, or clinically significant bleeding, clotting factor deficiencies should be treated.
  • Bleeding mainly occurs from the capillaries, and is usually from mucosal surfaces of the stomach and lung. Esophageal varices are uncommon in acute liver failure.
  • H2 receptor blocking agents help in protecting the mucosal surface of stomach from the acid due to stress.

Management of Hemodynamic and Metabolic Disturbances

  • Decreased tissue perfusion leading to poor oxygenation and multi-organ failure is a major concern in acute liver failure.
  • Patients should be resuscitated with normal saline first, then half normal saline containing 75 mEq/L of bicarbonate should be used. This fluid should be administered before the use of vasopressors.
  • For hypoglycemia, a dextrose solution should be used.
  • If a patient is not responding to fluid or vasopressors, the infusion rate should be slowed down to prevent intense vaso-constriction causing ischemia of tissues.
  • In patients progressing to acute renal failure care must be taken to avoid NSAIDs and nephrotoxic agents. Dialysis should be used in a continuous mode rather than intermittent mode.
  • Continuous monitoring of glucose and electrolytes is required as they may worsen the condition further.

Treatment for the Specific Underlying Cause

Acetaminophen Poisoning

    • Acetylcysteine is used for acetaminophen poisoning up to 72 hours after ingestion.
    • Acetylcysteine improves cerebral blood flow and increases transplant-free survival in patients with stage 1 or 2 encephalopathy due to hepatic failure of any cause.
    • Its treatment can increase prothrombin time, and give a false alarm of worsening liver failure.
      • 140 mg/kg orally followed by 70 mg/kg orally every 4 hours for an additional 17 doses or
      • 150 mg/kg in 5% dextrose intravenously over 15 minutes followed by 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours.

Mushroom Poisoning

Drug Induced Hepatoxicity

  • Drugs other than acetaminophen rarely cause dose induced toxicity.
  • The mechanism of toxicity is mostly due to idiosyncratic toxicity.
  • No specific antidotes exist for these idiosyncratic drug reactions.
  • Corticosteroids are not indicated unless a drug hypersensitivity such as DRESS syndrome (drug rash with eosinophilia and systemic symptoms) syndrome or an autoimmune reaction is suspected.

Chronic Viral Hepatitis

Herpes Simplex Hepatitis

Wilson's Disease

Autoimmune Hepatitis

HELLP Syndrome

  • Hepatic rupture or hemorrhage are fatal complications of HELLP syndrome requiring immediate resuscitation and intervention.
  • Early diagnosis of the complications, and delivery of the baby helps in improving the outcome.
  • Transplantation my be considered if there is postpartum deterioration.

Shock Liver

  • Treatment of underlying cause of ischemia in shock liver is very important, and determines the prognosis of the condition.
  • Transplantation is seldom indicated.

Budd-Chiari Syndrome

  • Transplantation is considered after confirming the diagnosis Budd-Chiari syndrome and excluding malignancy for venous decompression.[4]

Liver Support Systems

Liver support systems are support devices which help in resting the liver to provide it some time to recover. These can also be used as a bridge to transplantation. There are two kinds of devices; sorbent based artificial systems and cell based bio-artificial systems. There is no good evidence showing a decrease in mortality with their use in acute liver failure[5]. They are not currently recommended outside of clinical trials.

2011 AASLD Recommendations for Acute Liver Failure (DO NOT EDIT) [6]

General Measures (DO NOT EDIT)[6]

Class III
1. "Patients with ALF should be hospitalized and monitored frequently, preferably in an ICU."
2. "The precise etiology of ALF should be sought to guide further management decisions."

Encephalopathy and Intracranial Pressure (DO NOT EDIT) [6]

Class I
1. "In ALF patients at highest risk for cerebral edema (serum ammonia > 150 lM, grade 3/4 hepatic encephalopathy, acute renal failure, requiring vasopressors to maintain MAP), the prophylactic induction of hypernatremia with hypertonic saline to a sodium level of 145-155 mEq/L is recommended."
2. "Corticosteroids should not be used to control elevated ICP in patients with ALF."
Class II-2
1. "In the event of intracranial hypertension, a mannitol bolus (0.5-1.0 gm/kg body weight) is recommended as first-line therapy; however, the prophylactic administration of mannitol is not recommended."
Class II-3
1. "Short-acting barbiturates and the induction of hypothermia to a core body temperature of 34-35oC may be considered for intracranial hypertension refractory to osmotic agents as a bridge to liver transplantation."
Class III
1. "In early stages of encephalopathy, lactulose may be used either orally or rectally to effect a bowel purge, but should not be administered to the point of diarrhea, and may interfere with the surgical field by increasing bowel distention during liver transplantation."
2. "Patients who progress to high-grade hepatic encephalopathy (grade III or IV) should undergo endotracheal intubation."
3. "Seizure activity should be treated with phenytoin and benzodiazepines with short half-lives. Prophylactic phenytoin is not recommended."
4. "Intracranial pressure monitoring is recommended in ALF patients with high grade hepatic encephalopathy, in centers with expertise in ICP monitoring, in patients awaiting and undergoing liver transplantation."
5. "In the absence of ICP monitoring, frequent (hourly) neurological evaluation is recommended to identify early evidence of intracranial hypertension."

Infections (DO NOT EDIT) [6]

Class III
1. "Periodic surveillance cultures are recommended to detect bacterial and fungal pathogens as early as possible. Antibiotic treatment should be initiated promptly according to surveillance culture results at the earliest sign of active infection or deterioration (progression to high grade hepatic encephalopathy or elements of the SIRS)"
2. "Prophylactic antibiotics and antifungals have not been shown to improve overall outcomes in ALF and therefore cannot be advocated in all patients, particularly those with mild hepatic encephalopathy."

Bleeding and Coagulopathy (DO NOT EDIT) [6]

Class I
1. "Patients with ALF in the ICU should receive prophylaxis with H2 blocking agents or proton pump inhibitors (or sucralfate as a second-line agent) for acid-related gastrointestinal bleeding associated with stress."
Class III
1. "Replacement therapy for thrombocytopenia and/or prolonged prothrombin time is recommended only in the setting of hemorrhage or prior to invasive procedures."

Hemodynamic and Metabolic Disturbances (DO NOT EDIT) [6]

Class I
1. "If dialysis support is needed for acute renal failure, it is recommended that a continuous mode rather than an intermittent mode be used."
Class II
1. "Goals of circulatory support in patients with ALF are a MAP 75 mmHg and CPP 60-80 mmHg."
Class II-1
2. "Systemic vasopressor support with agents such as norepinephrine should be administered in volume refractory hypotension or to ensure adequate CPP. Vasopressin or terlipressin can be added to norepinephrine in norepinephrine-refractory cases, but should be used cautiously in severely encephalopathic patients with intracranial hypertension."
Class III
1. "Fluid resuscitation and maintenance of adequate intravascular volume are recommended on presentation in patients with ALF. The initial treatment of hypotension should be with intravenous normal saline."
2. "Pulmonary artery catheterization is rarely necessary in patients with ALF and is associated with significant morbidity. Instead, appropriate volume status should be ensured with a volume challenge."
3. "Metabolic homeostasis must be carefully maintained in ALF patients. Overall nutritional status as well as glucose, phosphate, potassium and magnesium levels should be monitored frequently, with expeditious correction of derangement's."

Acetaminophen Hepatotoxicity (DO NOT EDIT)[6]

Class I
1. "For patients with known or suspected acetaminophen overdose within 4 hours of presentation, give activated charcoal just prior to starting NAC dosing."
Class II-1
1. "Begin NAC promptly in all patients where the quantity of acetaminophen ingested, serum drug level or rising aminotransferases indicate impending or evolving liver injury."
Class III
1. "NAC may be used in cases of acute liver failure in which acetaminophen ingestion is possible or when knowledge of circumstances surrounding admission is inadequate but aminotransferases suggest acetaminophen poisoning."

Mushroom Poisoning (DO NOT EDIT) [6]

Class III
1. "In ALF patients with known or suspected mushroom poisoning, consider administration of penicillin G and N-acetylcysteine."
2. "Patients with acute liver failure secondary to mushroom poisoning should be listed for transplantation, as this procedure is often the only lifesaving option."

Drug Induced Hepatoxicity (DO NOT EDIT)[6]

Class I
1. "N-acetylcysteine may be beneficial for acute liver failure due to drug-induced liver injury."
Class III
1. "Obtain details (including onset of ingestion, amount and timing of last dose) concerning all prescription and non-prescription drugs, herbs and dietary supplements taken over the past year."
2. "Determine ingredients of non-prescription medications whenever possible."
3. "In the setting of acute liver failure due to possible drug hepatotoxicity, discontinue all but essential medications."

Viral Hepatitis (DO NOT EDIT)[6]

Class III
1. "Viral hepatitis A (and E) related acute liver failure must be treated with supportive care as no virus specific treatment has proven to be effective."
2. "Nucleos(t)ide analogues should be considered for hepatitis B-associated acute liver failure and for prevention of post-transplant recurrence."

Herpes Simplex Hepatitis (DO NOT EDIT)[6]

Class III
1. "Patients with known or suspected herpes virus or varicella zoster as the cause of acute liver failure should be treated with acyclovir (5-10 mg/kg IV every 8 hours) and may be considered for transplantation."

Wilson Disease (DO NOT EDIT)[6]

Class III
1. "To exclude Wilson disease one should obtain ceruloplasmin, serum and urinary copper levels, slit lamp examination for Kayser-Fleischer rings, hepatic copper levels when liver biopsy is feasible, and total bilirubin/alkaline phosphatase ratio."
2. "Patients in whom Wilson disease is the likely cause of acute liver failure must be promptly considered for liver transplantation."

Autoimmune Hepatitis (DO NOT EDIT)[6]

Class III
1. "Patients with coagulopathy and mild hepatic encephalopathy due to autoimmune hepatitis may be considered for corticosteroid treatment (prednisone, 40-60 mg/day)."
2. "Patients with autoimmune hepatitis should be considered for transplantation even while corticosteroids are being administered."

HELLP Syndrome (DO NOT EDIT)[6]

Class III
1. "For acute fatty liver of pregnancy or the HELLP syndrome, expeditious delivery of the infant is recommended.Transplantation may need to be considered if hepatic failure does not resolve quickly following delivery."

Shock Liver (DO NOT EDIT)[6]

Class III
1. "In ALF patients with evidence of ischemic injury, cardiovascular support is the treatment of choice."

Budd-Chiari Syndrome (DO NOT EDIT)[6]

Class II-3
1. "Hepatic vein thrombosis with acute hepatic failure is an indication for liver transplantation, provided underlying malignancy is excluded."

Therapeutic Approach

Shown below are lists of recommendations of therapeutic approachs of acute liver failure based on the 2011 American Association for the Study of Liver Diseases (AASLD) position paper on acute liver failure.[7]

Intensive Care Unit Management

Organ System Specific Issues Management Recommendations
Central Nervous System Cerebral edema and intracranial hypertension a) Intracranial pressure monitoring: (III)
❑ ICP monitoring with monitors when patients
❑ Present with high grade hepatic encephalopathy (grade III/IV)
❑ Are in centers with expertise in ICP monitoring
❑ Are awaiting and undergoing liver transplantation
❑ Correct coagulopathy before ICP monitoring with monitors
❑ In the absence of ICP monitors
❑ Hourly neurological evaluation
❑ Monitoring of serum ammonia levels
❑ Transcranial ultrasonography

b) Prophylactic hypertonic saline: (I):❑ Hypertonic saline i.v bolus (20 ml of 30% sodium chloride or 200 ml of 3% sodium chloride)[8] for prophylactic induction of hypernatremia in patients with

❑ Serum ammonia >150 μM
❑ Grade III/IV hepatic encephalopathy
Acute renal failure
Vasopressors requirement to maintain MAP
❑ Maintain serum sodium level of 145-155 mEq/L

c) Intracranial hypertension treatment:

❑ I line therapy: (II-2)
Mannitol i.v bolus (0.5-1.0 gm/kg of body weight or 2 ml of 20% solution/kg of body weight)[8]
❑ Administered as needed as long as serum osmolality <320 mOsm/L
❑ II line therapy: (if refractory to mannitol) (II-3)
Short-acting barbiturates
Hypothermia induction to a core body temperature of 34°-35°C
❑ Indomethacin i.v bolus (0.5 mg/kg) may be used when cerebral hyperemia is also present[8]
❑ Goals of intracranial hypertension treatment[9]
ICP <20 mmHg
CPP >60 mmHg
❑ Hyperventilate to PaCO2 of 25-30 mmHg (in case of impending herniation)[10]
Grade I/II encephalopathy ❑ Frequent neurological assessment with avoidance of stimulation and sedation
❑ Small doses of short-acting benzodiazepines in case of unmanageable agitation
❑ Stat brain CT to rule out other causes of altered mental status
❑ Consideration for transfer to a liver transplant facility and listing for transplantation at the earliest
Lactulose (possibly helpful and may interfere with surgical field by increasing bowel distention during liver transplantation) (III)
❑ Infection surveillance
❑ Antibiotic prophylaxis against infections (possibly helpful)
❑ Infection treatment as required
Grade III/IV encephalopathy Besides managing the patient similar to grade I/II encephalopathy
❑ Intubate trachea (might require sedation) (III)
❑ Muscle relaxants for intubation[11][12]
During intubation: Depolarizing neuro-muscular blocking agents
After intubation: Propofol
❑ Elevate head of bed to 30°[13]
Lidocaine administration during endotracheal suctioning
❑ Immediate treatment of seizures with phenytoin and benzodiazepines with short half-lives (III)
❑ ICP monitoring with devices
❑ Mannitol administration following severe elevation of ICP or first clinical sign of herniation
❑ Hypertonic saline administration to raise serum sodium to 145-155 mmol/L
❑ Hyperventilate patient in case of impending herniation
❑ Monitor and manage hemodynamic and renal parameters as well as glucose, electrolytes and acid/base status
Cardiovascular System Hemodynamic abnormalities ❑ Fluid resuscitation and maintenance of adequate intravascular volume (initiate hypotension treatment with intravenous normal saline) (III)
❑ Systemic vasopressor support (dopamine, epinephrine, norepinephrine) as needed (II-1)
Vasopressinorterlipressin added to norepinephrine in norepinephrine-refractory cases (used cautiously in severely encephalopathic patients with intracranial hypertension) (II-1)
❑ Ensure appropriate volume status with a volume challenge (pulmonary artery catheterization is rarely necessary since it is associated with significant morbidity) (III)
Echocardiography for low cardiac output and right ventricular failure
❑ Goals of circulatory support: (II)
MAP ≥75 mmHg
CPP 60-80 mmHg
Respiratory System Aspiration pneumonitis ❑ Neurologic observation to monitor level of consciousness
❑ Early endotracheal intubation for depressed level of consciousness
Hepatic System Hepatic dysfunction ❑ NAC administration (acetaminophen as well as non-acetaminophen ALF)
Metabolic and Renal System Metabolic abnormalities and renal failure ❑ Frequent monitoring and correction of derangements in glucose, potassium, magnesium and phosphate (III)
❑ Continuous modes of hemodialysis (if needed) (I)
Hematologic System Coagulopathy ❑ Replacement therapy for thrombocytopenia and/or prolonged prothrombin time with platelet and FFP transfusion respectively in the setting of active bleeding or before invasive procedure (III)
Vitamin K (5-10 mg subcutaneously) (at least one dose)[14]
❑ Plasmapheresis or recombinant activated factor VII (rFVIIa) in case of inadequate correction of severely elevated INR and risks of volume overload
❑ Maintenance of adequate platelet count
In the absence of bleeding: >10,000/mm3[15]
For performing invasive procedures: 50-70,000/ mm3

❑ Prophylaxis for stress ulceration: (I)

❑ I line: H2 blocker or PPI
❑ II line: Sucralfate
Immunologic System Infection ❑ Periodic surveillance for prompt initiation of antimicrobial treatment of infections at the earliest sign of active infection or deterioration (progression to high grade hepatic encephalopathy or elements of the SIRS) (III)
❑ Antibiotic prophylaxis (possibly helpful in patients with coagulopathy, organ failure, encephalopathy and in whom illness progression is considered likely - not proven) (III)

Etiology Specific Management

Etiology Diagnostic Indicators Management Recommendations
Acetaminophen toxicity ❑ H/o of acetaminophen intake (toxic dose >10 gm/day or >150 mg/kg)
❑ Acetaminophen in blood and/or urine
Aminotransferase levels >3500 IU/L with low bilirubin levels, in the absence of apparent hypotension or cardiovascular collapse (suspected acetaminophen toxicity in the absence of a positive history because acetaminophen is the leading cause of ALF at least in the United States and Europe)[16]
Activated charcoal:
1g/kg PO within 1 hour after drug ingestion (may be beneficial even when administered within 3-4 hours after ingestion)[17] and prior to starting NAC (I)
Nomogram (helps determining the likelihood of serious liver damage but does not exclude possible toxicity)
NAC:
140 mg/kg PO or through NGT (diluted to 5% solution), then 70 mg/kg PO q4h x 17 doses
or
IV loading dose of 150 mg/kg in 5% dextrose over 15 minutes, then maintenance dose of 50 mg/kg IV over the next 4 hours and then 100 mg/kg IV over the following 16 hours
*Promptly begin NAC (beneficial even when administered <48 hours after drug ingestion) in all patients with impending or evolving liver injury due to acetaminophen (II-1)
*NAC may be used in cases of ALF due to suspected acetaminophen poisoning (III)
*NAC is recommended even in case of non-acetaminophen ALF[18]
Acute fatty liver of pregnancy/HELLP ❑ Jaundice and hypertension
❑ Coagulopathy
❑ Thrombocytopenia
❑ Proteinuria
❑ Hypoglycemia
Steatosis in liver imaging or biopsy
❑ Early diagnosis and prompt delivery (III)
❑ Adequate supportive care
❑ Consider transplantation for postpartum deterioration (III)
Acute ischemic injury ❑ H/o cardiac arrest
❑ Any period of significant hypovolemia/hypotension, or severe CHF (hypotension is not documented always)
❑ Any associated renal dysfunction & muscle necrosis
❑ Elevated aminotransferase levels responding to fluid resuscitation
❑ Adequate cardiovascular support (III)
Autoimmune ❑ Positive serum autoantibodies (may be absent)
❑ Positive liver biopsy (confirms diagnosis when autoimmune hepatitis is suspected and autoantibodies are negative) (III)
Prednisolone (start with 40-60 mg/day, especially in the presence of coagulopathy and mild hepatic encephalopathy) (III)
❑ Consider transplantation and do not delay while awaiting response to steroid treatment (III)
Budd-Chiari ❑ Abdominal pain
❑ Ascites
❑ Hepatomegaly
❑ Blood tests positive for hypercoagulability
❑ Positive findings during liver imaging (CT, doppler USG, venography or magnetic resonance venography) (confirms diagnosis)
❑ Liver transplantation (provided underlying malignancy is excluded) (II-3)
Drug induced ❑ H/o hepatotoxic drug intake (usually idiosyncratic hepatotoxic drug intake within first 6 months after drug initiation; continuous usage of potentially hepatotoxic drug for more than 1 to 2 years is unlikely to cause de novo liver damage)
❑ H/o inclusive of details (including onset of ingestion, amount and timing of last dose) concerning all prescription and non-prescription drugs, herbs and dietary supplements taken over the past year (III)
❑ Determine ingredients of non-prescription medications whenever possible (III)
❑ Discontinue all but essential medications in the setting of possible drug hepatotoxicity (III)
❑ NAC (may be beneficial for ALF induced by drugs) (I)
Malignant infiltration ❑ Massive hepatomegaly
❑ Malignant infiltration in liver imaging or liver biopsy (confirms or excludes diagnosis) (III)
❑ Appropriate management of underlying malignancy
❑ Supportive care
Mushroom poisoning ❑ H/o recent mushroom intake
❑ Severe GI symptoms like nausea, vomiting and diarrhea within hours or a day of ingestion (suspected mushroom poisoning in the absence of a positive history)
❑ Early gastric lavage and activated charcoal administration
Penicillin G 300,000-1 million units/kg/day
or
Silibinin 30-40 mg/kg/day IV or PO, 3-4 days (silymarin in Europe and south America; milk thistle in north America)[19]
❑ NAC (III)
❑ Liver transplantation (the only lifesaving option) (III)
❑ Fluid resuscitation (as needed)
Viral ❑ Toxically appearing patients with skin lesions (HSV)
❑ Positive hepatitis virus serology
HSV positive liver biopsy
❑ Supportive treatment (no virus specific treatment proven to be effective) (III)
❑ Nucleoside and nucleotide analogues (for HBV associated ALF) (III)
Acyclovir (5-10 mg/kg every 8 hours for at least 7 days for HSV or VZV) (III)
Wilson's disease ❑ KF ring
❑ Serum bilirubin >20 mg/dL,
❑ Bilirubin:alkaline phosphatase >2.0
❑ Low serum ceruloplasmin
❑ Elevated serum & urine copper
❑ High copper levels in liver biopsy (III)
❑ Liver transplantation (III)
❑ Dialysis or hemofiltration or plasmapheresis or plasma exchange
Intermediate etiology ❑ Etiology undetermined after all evaluation ❑ Review drug and toxin intake H/o
❑ Transjugular biopsy (for further evaluation of possible mailgnancy, Wilson disease, autoimmune hepatitis and viral hepatitis) (III)

Transplantation

Liver Transplantation Recommendations
Prognostic scoring systems Currently available and widely applied prognostic scoring systems (King’s College Hospital criteria-KCH Criteria,[20] Clichy Criteria,[21] and Japanese Criteria[22]) do not adequately predict outcome and determine candidacy for liver transplantation, thus not recommending the entire reliance entirely upon these guidelines (III)
Urgent hepatic transplantation Urgent hepatic transplantation is indicated when prognostic indicators suggest a high likelihood of death (II-3)
In the setting of limited organ supply In the setting of limited organ supply, either living donor or auxiliary liver transplantation may be considered. But its use remains controversial (II-3)
Liver support systems Currently available liver support systems are not recommended outside clinical trials and their future in management of ALF remains unclear(II-1)

Intensive Care Unit Management

Organ System Specific Issues Management Recommendations
Central Nervous System Cerebral edema and intracranial hypertension a) Intracranial pressure monitoring: (III)
❑ ICP monitoring with monitors when patients
❑ Present with high grade hepatic encephalopathy (grade III/IV)
❑ Are in centers with expertise in ICP monitoring
❑ Are awaiting and undergoing liver transplantation
❑ Correct coagulopathy before ICP monitoring with monitors
❑ In the absence of ICP monitors
❑ Hourly neurological evaluation
❑ Monitoring of serum ammonia levels
❑ Transcranial ultrasonography

b) Prophylactic hypertonic saline: (I):❑ Hypertonic saline i.v bolus (20 ml of 30% sodium chloride or 200 ml of 3% sodium chloride)[8] for prophylactic induction of hypernatremia in patients with

❑ Serum ammonia >150 μM
❑ Grade III/IV hepatic encephalopathy
Acute renal failure
Vasopressors requirement to maintain MAP
❑ Maintain serum sodium level of 145-155 mEq/L

c) Intracranial hypertension treatment:

❑ I line therapy: (II-2)
Mannitol i.v bolus (0.5-1.0 gm/kg of body weight or 2 ml of 20% solution/kg of body weight)[8]
❑ Administered as needed as long as serum osmolality <320 mOsm/L
❑ II line therapy: (if refractory to mannitol) (II-3)
Short-acting barbiturates
Hypothermia induction to a core body temperature of 34°-35°C
❑ Indomethacin i.v bolus (0.5 mg/kg) may be used when cerebral hyperemia is also present[8]
❑ Goals of intracranial hypertension treatment[9]
ICP <20 mmHg
CPP >60 mmHg
❑ Hyperventilate to PaCO2 of 25-30 mmHg (in case of impending herniation)[10]
Grade I/II encephalopathy ❑ Frequent neurological assessment with avoidance of stimulation and sedation
❑ Small doses of short-acting benzodiazepines in case of unmanageable agitation
❑ Stat brain CT to rule out other causes of altered mental status
❑ Consideration for transfer to a liver transplant facility and listing for transplantation at the earliest
Lactulose (possibly helpful and may interfere with surgical field by increasing bowel distention during liver transplantation) (III)
❑ Infection surveillance
❑ Antibiotic prophylaxis against infections (possibly helpful)
❑ Infection treatment as required
Grade III/IV encephalopathy Besides managing the patient similar to grade I/II encephalopathy
❑ Intubate trachea (might require sedation) (III)
❑ Muscle relaxants for intubation[11][12]
During intubation: Depolarizing neuro-muscular blocking agents
After intubation: Propofol
❑ Elevate head of bed to 30°[13]
Lidocaine administration during endotracheal suctioning
❑ Immediate treatment of seizures with phenytoin and benzodiazepines with short half-lives (III)
❑ ICP monitoring with devices
❑ Mannitol administration following severe elevation of ICP or first clinical sign of herniation
❑ Hypertonic saline administration to raise serum sodium to 145-155 mmol/L
❑ Hyperventilate patient in case of impending herniation
❑ Monitor and manage hemodynamic and renal parameters as well as glucose, electrolytes and acid/base status
Cardiovascular System Hemodynamic abnormalities ❑ Fluid resuscitation and maintenance of adequate intravascular volume (initiate hypotension treatment with intravenous normal saline) (III)
❑ Systemic vasopressor support (dopamine, epinephrine, norepinephrine) as needed (II-1)
Vasopressinorterlipressin added to norepinephrine in norepinephrine-refractory cases (used cautiously in severely encephalopathic patients with intracranial hypertension) (II-1)
❑ Ensure appropriate volume status with a volume challenge (pulmonary artery catheterization is rarely necessary since it is associated with significant morbidity) (III)
Echocardiography for low cardiac output and right ventricular failure
❑ Goals of circulatory support: (II)
MAP ≥75 mmHg
CPP 60-80 mmHg
Respiratory System Aspiration pneumonitis ❑ Neurologic observation to monitor level of consciousness
❑ Early endotracheal intubation for depressed level of consciousness
Hepatic System Hepatic dysfunction ❑ NAC administration (acetaminophen as well as non-acetaminophen ALF)
Metabolic and Renal System Metabolic abnormalities and renal failure ❑ Frequent monitoring and correction of derangements in glucose, potassium, magnesium and phosphate (III)
❑ Continuous modes of hemodialysis (if needed) (I)
Hematologic System Coagulopathy ❑ Replacement therapy for thrombocytopenia and/or prolonged prothrombin time with platelet and FFP transfusion respectively in the setting of active bleeding or before invasive procedure (III)
Vitamin K (5-10 mg subcutaneously) (at least one dose)[14]
❑ Plasmapheresis or recombinant activated factor VII (rFVIIa) in case of inadequate correction of severely elevated INR and risks of volume overload
❑ Maintenance of adequate platelet count
In the absence of bleeding: >10,000/mm3[15]
For performing invasive procedures: 50-70,000/ mm3

❑ Prophylaxis for stress ulceration: (I)

❑ I line: H2 blocker or PPI
❑ II line: Sucralfate
Immunologic System Infection ❑ Periodic surveillance for prompt initiation of antimicrobial treatment of infections at the earliest sign of active infection or deterioration (progression to high grade hepatic encephalopathy or elements of the SIRS) (III)
❑ Antibiotic prophylaxis (possibly helpful in patients with coagulopathy, organ failure, encephalopathy and in whom illness progression is considered likely - not proven) (III)
Etiology Diagnostic Indicators Management Recommendations
Acetaminophen toxicity ❑ H/o of acetaminophen intake (toxic dose >10 gm/day or >150 mg/kg)
❑ Acetaminophen in blood and/or urine
Aminotransferase levels >3500 IU/L with low bilirubin levels, in the absence of apparent hypotension or cardiovascular collapse (suspected acetaminophen toxicity in the absence of a positive history because acetaminophen is the leading cause of ALF at least in the United States and Europe)[16]
Activated charcoal:
1g/kg PO within 1 hour after drug ingestion (may be beneficial even when administered within 3-4 hours after ingestion)[17] and prior to starting NAC (I)
Nomogram (helps determining the likelihood of serious liver damage but does not exclude possible toxicity)
NAC:
140 mg/kg PO or through NGT (diluted to 5% solution), then 70 mg/kg PO q4h x 17 doses
or
IV loading dose of 150 mg/kg in 5% dextrose over 15 minutes, then maintenance dose of 50 mg/kg IV over the next 4 hours and then 100 mg/kg IV over the following 16 hours
*Promptly begin NAC (beneficial even when administered <48 hours after drug ingestion) in all patients with impending or evolving liver injury due to acetaminophen (II-1)
*NAC may be used in cases of ALF due to suspected acetaminophen poisoning (III)
*NAC is recommended even in case of non-acetaminophen ALF[18]
Acute fatty liver of pregnancy/HELLP ❑ Jaundice and hypertension
❑ Coagulopathy
❑ Thrombocytopenia
❑ Proteinuria
❑ Hypoglycemia
Steatosis in liver imaging or biopsy
❑ Early diagnosis and prompt delivery (III)
❑ Adequate supportive care
❑ Consider transplantation for postpartum deterioration (III)
Acute ischemic injury ❑ H/o cardiac arrest
❑ Any period of significant hypovolemia/hypotension, or severe CHF (hypotension is not documented always)
❑ Any associated renal dysfunction & muscle necrosis
❑ Elevated aminotransferase levels responding to fluid resuscitation
❑ Adequate cardiovascular support (III)
Autoimmune ❑ Positive serum autoantibodies (may be absent)
❑ Positive liver biopsy (confirms diagnosis when autoimmune hepatitis is suspected and autoantibodies are negative) (III)
Prednisolone (start with 40-60 mg/day, especially in the presence of coagulopathy and mild hepatic encephalopathy) (III)
❑ Consider transplantation and do not delay while awaiting response to steroid treatment (III)
Budd-Chiari ❑ Abdominal pain
❑ Ascites
❑ Hepatomegaly
❑ Blood tests positive for hypercoagulability
❑ Positive findings during liver imaging (CT, doppler USG, venography or magnetic resonance venography) (confirms diagnosis)
❑ Liver transplantation (provided underlying malignancy is excluded) (II-3)
Drug induced ❑ H/o hepatotoxic drug intake (usually idiosyncratic hepatotoxic drug intake within first 6 months after drug initiation; continuous usage of potentially hepatotoxic drug for more than 1 to 2 years is unlikely to cause de novo liver damage)
❑ H/o inclusive of details (including onset of ingestion, amount and timing of last dose) concerning all prescription and non-prescription drugs, herbs and dietary supplements taken over the past year (III)
❑ Determine ingredients of non-prescription medications whenever possible (III)
❑ Discontinue all but essential medications in the setting of possible drug hepatotoxicity (III)
❑ NAC (may be beneficial for ALF induced by drugs) (I)
Malignant infiltration ❑ Massive hepatomegaly
❑ Malignant infiltration in liver imaging or liver biopsy (confirms or excludes diagnosis) (III)
❑ Appropriate management of underlying malignancy
❑ Supportive care
Mushroom poisoning ❑ H/o recent mushroom intake
❑ Severe GI symptoms like nausea, vomiting and diarrhea within hours or a day of ingestion (suspected mushroom poisoning in the absence of a positive history)
❑ Early gastric lavage and activated charcoal administration
Penicillin G 300,000-1 million units/kg/day
or
Silibinin 30-40 mg/kg/day IV or PO, 3-4 days (silymarin in Europe and south America; milk thistle in north America)[19]
❑ NAC (III)
❑ Liver transplantation (the only lifesaving option) (III)
❑ Fluid resuscitation (as needed)
Viral ❑ Toxically appearing patients with skin lesions (HSV)
❑ Positive hepatitis virus serology
HSV positive liver biopsy
❑ Supportive treatment (no virus specific treatment proven to be effective) (III)
❑ Nucleoside and nucleotide analogues (for HBV associated ALF) (III)
Acyclovir (5-10 mg/kg every 8 hours for at least 7 days for HSV or VZV) (III)
Wilson's disease ❑ KF ring
❑ Serum bilirubin >20 mg/dL,
❑ Bilirubin:alkaline phosphatase >2.0
❑ Low serum ceruloplasmin
❑ Elevated serum & urine copper
❑ High copper levels in liver biopsy (III)
❑ Liver transplantation (III)
❑ Dialysis or hemofiltration or plasmapheresis or plasma exchange
Intermediate etiology ❑ Etiology undetermined after all evaluation ❑ Review drug and toxin intake H/o
❑ Transjugular biopsy (for further evaluation of possible mailgnancy, Wilson disease, autoimmune hepatitis and viral hepatitis) (III)

Transplantation

Liver Transplantation Recommendations
Prognostic scoring systems Currently available and widely applied prognostic scoring systems (King’s College Hospital criteria-KCH Criteria,[20] Clichy Criteria,[21] and Japanese Criteria[22]) do not adequately predict outcome and determine candidacy for liver transplantation, thus not recommending the entire reliance entirely upon these guidelines (III)
Urgent hepatic transplantation Urgent hepatic transplantation is indicated when prognostic indicators suggest a high likelihood of death (II-3)
In the setting of limited organ supply In the setting of limited organ supply, either living donor or auxiliary liver transplantation may be considered. But its use remains controversial (II-3)
Liver support systems Currently available liver support systems are not recommended outside clinical trials and their future in management of ALF remains unclear(II-1)
Liver Transplantation Recommendations
Prognostic scoring systems Currently available and widely applied prognostic scoring systems (King’s College Hospital criteria-KCH Criteria,[20] Clichy Criteria,[21] and Japanese Criteria[22]) do not adequately predict outcome and determine candidacy for liver transplantation, thus not recommending the entire reliance entirely upon these guidelines (III)
Urgent hepatic transplantation Urgent hepatic transplantation is indicated when prognostic indicators suggest a high likelihood of death (II-3)
In the setting of limited organ supply In the setting of limited organ supply, either living donor or auxiliary liver transplantation may be considered. But its use remains controversial (II-3)
Liver support systems Currently available liver support systems are not recommended outside clinical trials and their future in management of ALF remains unclear(II-1)

References

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  3. Czaja AJ (2012). "Acute and Acute Severe (Fulminant) Autoimmune Hepatitis". Digestive Diseases and Sciences. doi:10.1007/s10620-012-2445-4. PMID 23090425. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
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  5. Freeman RB, Steffick DE, Guidinger MK, Farmer DG, Berg CL, Merion RM (2008). "Liver and intestine transplantation in the United States, 1997-2006". American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 8 (4 Pt 2): 958–76. doi:10.1111/j.1600-6143.2008.02174.x. PMID 18336699. Retrieved 2012-10-26. Unknown parameter |month= ignored (help)
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  11. 11.0 11.1 Stravitz, RT.; Kramer, DJ. (2009). "Management of acute liver failure". Nat Rev Gastroenterol Hepatol. 6 (9): 542–53. doi:10.1038/nrgastro.2009.127. PMID 19652652. Unknown parameter |month= ignored (help)
  12. 12.0 12.1 Wijdicks, EF.; Nyberg, SL. (2002). "Propofol to control intracranial pressure in fulminant hepatic failure". Transplant Proc. 34 (4): 1220–2. PMID 12072321. Unknown parameter |month= ignored (help)
  13. 13.0 13.1 Durward, QJ.; Amacher, AL.; Del Maestro, RF.; Sibbald, WJ. (1983). "Cerebral and cardiovascular responses to changes in head elevation in patients with intracranial hypertension". J Neurosurg. 59 (6): 938–44. doi:10.3171/jns.1983.59.6.0938. PMID 6631516. Unknown parameter |month= ignored (help)
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  16. 16.0 16.1 Ostapowicz, G.; Fontana, RJ.; Schiødt, FV.; Larson, A.; Davern, TJ.; Han, SH.; McCashland, TM.; Shakil, AO.; Hay, JE. (2002). "Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States". Ann Intern Med. 137 (12): 947–54. PMID 12484709. Unknown parameter |month= ignored (help)
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  21. 21.0 21.1 21.2 Bernuau, J.; Rueff, B.; Benhamou, JP. (1986). "Fulminant and subfulminant liver failure: definitions and causes". Semin Liver Dis. 6 (2): 97–106. doi:10.1055/s-2008-1040593. PMID 3529410. Unknown parameter |month= ignored (help)
  22. 22.0 22.1 22.2 Mochida, S.; Nakayama, N.; Matsui, A.; Nagoshi, S.; Fujiwara, K. (2008). "Re-evaluation of the Guideline published by the Acute Liver Failure Study Group of Japan in 1996 to determine the indications of liver transplantation in patients with fulminant hepatitis". Hepatol Res. 38 (10): 970–9. doi:10.1111/j.1872-034X.2008.00368.x. PMID 18462374. Unknown parameter |month= ignored (help)

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