Acute liver failure resident survival guide

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

Definitions

Acute Liver Failure

Evidence of coagulation abnormality (INR ≥1.5) and any degree of alteration in mental status in the absence of pre exisiting cirrhosis and any illness of <26 weeks duration is defined as acute liver failure. Few exceptions that are included in spite of their presentation with cirrhosis are Wilson disease, vertically-acquired HBV, and autoimmune hepatitis if they have been recognized for <26 weeks. When the above presentation duration is up to 26 weeks, acute liver failure is the better terminology to be used when compared to terms like fulminant hepatic failure, fulminant hepatitis or necrosis, hyperacute, acute and subacute liver failure.

Hepatic Encephalopathy

Based on their clinical manifestation, different grades of hepatic encephalopathy are defined as follows

Grades	Clinical Features
I	Changes in behavior, minimal changes in level of consciousness
II	Inappropriate behavior, gross disorientation, drowsiness, possibly asterixis
III	Marked confusion, incoherent speech, mostly sleeping but arousable to vocal stimuli
IV	Comatose, unresponsive to pain, decorticate or decerebrate posturing

Causes

Life Threatening Causes

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.

• Cocaine
• Idiosyncratic hypersensitivity reactions
• Mushroom poisoning (Amanita phalloides)
• Shock or hypoperfusion

Common Causes

• Autoimmune hepatitis
• Acetaminophen toxicity
• Viral hepatitis
• Shock or hypoperfusion

Management

Detailed H/o & PE H/o ❑ Altered mental status ❑ Exposure to viral infections ❑ Drug and toxin intake PE ❑ Mental status ❑ Stigmata of chronic liver disease

Initial Laboratory Analysis ❑ Prothrombin time/INR Serum chemistries ❑ Sodium ❑ Potassium ❑ Chloride ❑ Bicarbonate ❑ Calcium ❑ Magnesium ❑ Phosphate ❑ Glucose ❑ Blood Urea Nitrogen ❑ Creatinine ❑ AST ❑ ALT ❑ Alkaline phosphatase ❑ GGT ❑ Total bilirubin ❑ Albumin ❑ Complete blood count ❑ Ammonia ❑ Arterial blood gas ❑ Arterial lactate ❑ Amylase and lipase ❑ Acetaminophen level ❑ Toxicology screen ❑ Viral hepatitis serologies (anti-HAV IgM, HBsAg, anti-HBc IgM, anti-HEV, anti-HCV, HCV RNA, HSV1 IgM, VZV) ❑ Autoimmune markers (ANA, ASMA, Immunoglobulin levels) ❑ Ceruloplasmin level† ❑ Blood type and screen ❑ Pregnancy test (females) ❑ HIV-1, HIV-2‡

Dx: Acute liver failure Dx criteria: INR ≥1.5 and any degree of alteration in mental status in the absence of pre exisiting cirrhosis and any illness of <26 weeks duration

Mandatory ICU admission

ICU management Etiology specific management

Consider transplantation

^†In case of Wilson disease consideration (e.g., in patients less than 40 years without obvious explanation for ALF)
^‡Implications for potential liver transplantation

ICU Management

Specific Issues	Management Recommendations
Cerebral edema and intracranial hypertension	a) Intracranial pressure monitoring: 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 Hourly neurological evaluation in the absence of ICP monitors b) Prophylactic hypertonic saline: Prophylactic induction of hypernatremia with hypertonic saline to a sodium level of 145-155 mEq/L in patients with *Serum ammonia >150 μM *Grade III/IV hepatic encephalopathy *Acute renal failure *Vasopressors requirement to maintain MAP c) Intracranial hypertension treatment: *I line therapy: Mannitol bolus (0.5-1.0 gm/kg body weight) *II line therapy: Short-acting barbiturates and induction of hypothermia to a core body temperature of 34°-35°C (if refractory to mannitol) *Hyperventilate patient to PaCO2 of 25-30 mmHg (effects may be short-lived and are useful for impending herniation)
Grade I/II encephalopathy	a) Frequent neurological assessment, avoid stimulation and avoid sedation if possible (consider small doses of short-acting benzodiazepines in case of unmanageable agitation) b) Consider transfer to liver transplant facility and listing for transplantation at the earliest c) Include a stat brain CT to rule out other causes of altered mental status d) Infection surveillance and treatment required e) Antibiotic prophylaxis against infections (possibly helpful) f) Lactulose (possibly helpful and may interfere with surgical field by increasing bowel distention during liver transplantation)
Grade III/IV encephalopathy	Besides managing the patient similar to grade I/II encephalopathy a) Intubate trachea (might require sedation) *During intubation: On-depolarizing neuro-muscular blocking agents After intubation: Propofol b) Administer lidocaine during endotracheal suctioning c) Elevate head of bed to 30° d) Consider ICP monitoring with device e) Mannitol administered when severe elevation of ICP or first clinical sign of herniation noted f) Administer hypertonic saline to raise serum sodium to 145-155 mmol/L g) Hyperventilate patient (effects may be short-lived and are useful for impending herniation) h) Immediate treatment of seizures i) Monitoring and management of hemodynamic and renal parameters as well as glucose, electrolytes and acid/base status
Infection	a) 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) b) Antibiotic prophylaxis possibly helpful (not proven)
Coagulopathy	a) Vitamin K (5-10 mg subcutaneously) administered routinely (at least one dose) b) In the setting of active bleeding or before invasive procedure, consider administration of FFP along with recombinant activated factor VII c) Prophylaxis for stress ulceration: *I line: H2 blocker or PPI *II line: Sucralfate
Hemodynamics and renal failure	a) Fluid resuscitation and maintenance of adequate intravascular volume (initiate hypotension treatment with with intravenous normal saline) b) Systemic vasopressor support (dopamine, epinephrine, norepinephrine) as needed c) Vasopressin or terlipressin added to norepinephrine in norepinephrine-refractory cases (used cautiously in severely encephalopathic patients with intracranial hypertension) d) Goals of circulatory support: *MAP ≥75 mmHg *CPP 60-80 mmHg e) Continuous modes of hemodialysis (if needed) f) Avoid nephrotoxic agents
Metabolic abnormalities	a) Frequently monitor and correct derangements in glucose, potassium, magnesium and phosphate b) Consider nutrition support with enteral feedings if possible or total parenteral nutrition

Etiology Specific Management

Etiology	Diagnostic Indicators	Management Recommendations
Acetaminophen toxicity	a) H/o: Acetaminophen intake (toxic dose >10 gm/day or >150 mg/kg) b) Labs: Acetaminophen in blood and urine c) Suspected if no H/o but aminotransferase levels >3500 IU/L with low bilirubin levels, in the absence of apparent hypotension or cardiovascular collapse (because acetaminophen is the leading cause of ALF at least in the United States and Europe)	a) Activated charcoal: Administer 1g/kg PO within 1 hour after drug ingestion (may be beneficial even when administered within 3-4 hours after ingestion) b) Nomogram Plotting helps determining the likelihood of serious liver damage (but it does not exclude possible toxicity) c) NAC: *Administer NAC at the earliest (beneficial even when administered within 48 hours after drug ingestion) *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 *Anticipate nausea and vomiting (with rapid infusion or oral NAC) and rarely urticaria or bronchospasm d) NAC administration is recommended even in case of non-acetaminophen acute liver failure (eg. drug-induced liver injury and hepatitis B) since it improves outcome
Acute fatty liver of pregnancy/HELLP	a) H/o and PE: Jaundice and hypertension b) Labs: Coagulopathy, thrombocytopenia, proteinuria ± hypoglycemia c) Liver imaging or biopsy: Steatosis	a) Early diagnosis and prompt delivery b) Supportive care c) Consider transplantation for postpartum deterioration
Acute ischemic injury	a) H/o and PE: *Cardiac arrest, any period of significant hypovolemia/hypotension, or severe CHF (hypotension is not documented always) *Associated renal dysfunction & muscle necrosis b) Labs: Elevated aminotransferase levels responding to fluid resuscitation	Cardiovascular support
Autoimmune	a) Labs: Serum autoantibodies (may be absent) b) Liver biopsy (confirms diagnosis when autoimmune hepatitis is suspected and autoantibodies are negative)	a) Administer prednisolone (start with 40-60 mg/day, especially in the presence of coagulopathy and mild hepatic encephalopathy) b) Consider transplantation and do not delay while awaiting response to steroid treatment
Budd-Chiari	a) H/o and PE: Abdominal pain, ascites and hepatomegaly b) Labs: Tests to identify hypercoagulability c) Liver imaging: CT, doppler USG, venography or magnetic resonance venography (confirms diagnosis)	Transplantation (provided underlying malignancy is excluded)
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)	a) Discontinue all possible medications except essential drugs b) NAC may be beneficial
Malignant infiltration	a) PE: Massive hepatomegaly b) Liver imaging & biopsy: Malignant infiltration	a) Treat the underlying malignancy accordingly b) Supportive treatment
Mushroom poisoning	a) H/o: Recent mushroom intake b) Suspected if no H/o but severe GI symptoms like nausea, vomiting and diarrhea within hours or a day of ingestion	a) Early gastric lavage and activated charcoal administration b) 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) c) Fluid resuscitation as needed d) Listed for transplantation (the only lifesaving option)
Viral	a) PE: Toxically appearing patients with skin lesions in HSV b) Labs: Positive hepatitis virus serology c) Liver biopsy: HSV	a) Supportive treatment (no virus specific treatment proven to be effective) b) HBV: *Nucleoside analogues (lamivudine) considered for acute hepatitis B *Prophylactic as well as post therapy treatment with nucleotide analogues considered for reactivation of chronic or inactive hepatitis B in the setting of chemotherapy or immunosuppression *Both prevent post transplant recurrence c) HSV or VZV: *Acyclovir (5-10 mg/kg every 8 hours for at least 7 days) for suspected or documented cases *Consider transplantation
Wilson's disease	a) PE: KF ring b) Labs: Serum bilirubin >20 mg/dL, bilirubin:alkaline phosphatase >2.0, low serum ceruloplasmin, elevated serum & urine copper c) Liver biopsy: High copper levels	a) Copper lowering measures: Dialysis or hemofiltration or plasmapheresis or plasma exchange b) Consider transplantation
Intermediate etiology	Etiology undetermined after all evaluation	a) Review drug and toxin intake H/o b) Transjugular biopsy for further evaluation of possible mailgnancy, Wilson disease, autoimmune hepatitis and viral hepatitis

Do's

ICU Management

• Cerebral edema and intracranial hypertension:
  • Monitor ICP which also allows assessment of cerebral perfusion pressure (CPP), in order to avoid hypoperfusion of the brain
  • Correct coagulopathy that reduces bleeding risk and wider use of ICP monitors
  • Goal in management of ICH is lowering ICP (generally to <20 mmHg) while preserving CPP (>60 mmHg) with osmotically-active agents and/or vasopressors
  • Mannitol can be administered as needed as long as the serum osmolality is <320 mOsm/L
• Grade III/IV encephalopathy:
  • Treat seizure activity with phenytoin and benzodiazepines with short half-lives

• Transplant center:
  • Place patient immediately on the transplant list if progression of disease is rapid
• During initial evaluation:
  • In detailed H/o: Include H/o viral infection exposure, drug and toxin intake
  • In detailed PE: Look for stigmata of chronic liver disease
  • In lab tests: Calculate bilirubin:alkaline phosphatase ratio if Wilson disease suspected (e.g., in patients <40 years without obvious explanation for ALF). Include hepatitis E virus serology in migrants from endemic region.
• During monitoring for cerebral edema and increased ICP:
  • Include ICP monitoring when patient meets all eligible criteria for liver transplantation, encephalopathy is grade IV, CT head is consistent with edema without hemorrhage, PT is corrected to INR <1.5, and platelet count >100,000/mm3
  • Rule out or correct coagulopathy
  • Rule out intracerebral hemorrhage and other intracranial causes of altered mental status with CT head
  • ICP monitors are placed preferably in subdural space in OR
  • Other methods of monitoring that are in various stages of evaluation are transcranial doppler ultrasonography, near-infrared spectrophotometry, and measurement of serum S-100 beta and neuronal specific enolase
  • Target values during monitoring: ICP <20-25 mmHg and CPP 50-60 mmHg
• To prevent cerebral edema and increased ICP:
  • Administer 3% NS at 0.1-1 ml/kg/hr IV infusion
  • Maintain serum sodium between 145-155 mEq/dL and hold if serum osmolality is >360 mOsm/L
• To prevent coagulopathy:
  • Administer 5-10 mg of Inj. vitamin K SC
  • Administer cryoprecipitate if serum fibrinogen <100 mg/dL
  • Maintain platelet count around 20,000/mm3
• Avoid drugs:
  • Especially aminoglycosides
• Prophylactic antibiotics
  • Cefotaxime: 100-200 mg/kg/day IV; every 6-8 hours
  • If allergic to penicillin, meropenem: 20-40 mg/kg IV; every 8 hours
  • Flucanazole: 3-12 mg/kg IV; daily
  • In case of catheter related sepsis and suspected MRSA, vancomycin: 40 mg/kg/day IV; every 6-8 hours
  • Administer when
    • Infectious surveillance is positive
    • Encephalopathy is progressing to grade III/IV
    • There is gastrointestinal bleeding
    • Hypotension is refractory
    • Components of systemic inflammatory response syndrome (SIRS) are present
• For anticipated acetaminophen toxicity:
  • Administer NAC: 150 mg/kg IV over first 1 hour, 50 mg/kg IV over next 4 hours, 100 mg/kg IV over next 16 hours, 150 mg/kg IV over next 24 hours. Thereafter administer 70 mg/kg PO daily until discharge or transplantation.
• To prevent nutritional deficiency:
  • Eternal feeding
    • Protein 60 g/day
    • Hold if ammonia >200 mcg/dL
  • If eternal feeding is contraindicated, start parental feeding
    • IV D10 1/4 NS, maintain sodium <3 mEq/kg/day
    • Protein 0.5 g/kg/day
    • Hold if ammonia >200 mcg/dL

Etiology Specific Management

• Autoimmune hepatitis:
  • Consider prednisolone in patients with early stage acute liver failure and without multi-organ failure
• Budd-Chiari:
  • Rule out malignancy, malignancy associated coagulopathy and other thrombotic disorders before transplantation
• Drug induced:
  • 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
• Malignant infiltration:
  • Look for carcinoma of breast, small cell carcinoma of lung, lymphoma and melanoma (the common causes of metastatic liver infiltration)
• Viral:
  • Hepatitis E is considered in anyone with recent travel to an endemic area (Russia, Pakistan, Mexico, or India)
  • Suspect HSV during pregnancy and in immunocompromised patients
• Intermediate etiology:
  • Acetaminophen, autoimmune hepatitis and malignancies are the causes that represent indeterminate acute liver failure

Complication Specific Management

• Ascites:
  • Administer lasix (160 mg) and aldactone (400 mg) at 1:2.5
• Cerebral edema and increased ICP:
  • Mannitol: 0.5-1 g/kg; once or twice daily; hold if serum osmolality is >320 mOsm/L
  • Hyperventilate to PaCO2 of 25-30 mmHg
  • 3% NS: 0.1-1 ml/kg/hr; maintain serum sodium between 145-155 mEq/dL; hold if serum osmolality is >360 mOsm/L
• Coagulopathy:
  • Platelet transfusion until platelet count >50,000/mm3
  • rFVIIa: 40 mg/kg IV
• Hemodynamic instability:
  • Fluid resuscitation with target mean arterial pressure 50-60 mmHg and target CPP 60-80 mmHg
  • Add hydrocortisone in case of septic shock
• Grade II hepatic encephalopathy:
  • Add short acting BZD only when there is unimmaginable agitation
  • Ammonia >200 mcg/dL:
    • Lactulose 30-45 mg/d PO; 3-4 times a day
    • Target <50 mcg/dL
  • Persistently ammonia >50 mcg/dL:
    • Neomycin <12y≥ rifaximin
  • Persistently ammonia >200 mcg/dL:
    • Continuous venovenous hemodialysis for 3-4 hours
• Renal failure:
  • Continuous venovenous hemodialysis following symptomatic uremia, untraceable hyperkalemia and metabolic acidosis
• Add neurology, neurosurgery, hepatology, nephrology and transplant surgeon consult as needed.

Dont's

• Do not rule out acetaminophen induced hepatotoxicity, however low or absent levels of the drug might be, since the time of ingestion may be relatively remote or unknown, especially when overdose may have been unintentional or occurred over several days
• Do not administer protein if ammonia >200 mcg/dL.
• Do not administer penicillamine in the treatment of acute liver failure caused by Wilson disease because of the risk of hypersensitivity to this agent
• Stop administering mannitol if serum osmolality is >320 mOsm/L.
• Stop administering 3% NS if serum osmolality is >360 mOsm/L.
• Do not use sedatives in encephalopathy except during unimmaginable agitations during grade II hepatic encephalopathy.
• Do not administer prophylactic phenytoin for seizures.

References

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