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
• 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

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)
Grade I/II Encephalopathy	a) Frequent neurological assessment, avoid stimulation and avoid sedation if possible (consider treating the patient with 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)
Grade III/IV Encephalopathy	Besides managing the patient similar to grade I/II encephalopathy a) Intubate trachea (might require sedation) b) Elevate head of bed to 30° c) Consider ICP monitoring with device d) Mannitol administered when severe elevation of ICP or first clinical sign of herniation noted e) Administer hypertonic saline to raise serum sodium to 145-155 mmol/L f) Hyperventilate the patient (effects may be short-lived and are useful for impending herniation) g) Immediate treatment of seizures
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
Metabolic abnormalities

Etiology Specific Management

Etiology	Diagnostic Indicators	Management
Acetaminophen toxicity	a) H/o: Acetaminophen intake b) Labs: Acetaminophen in blood and urine c) Suspected if no H/o but aminotransferase levels are elevated (>3500 IU/L)	a) Administer activated charcoal (1g/kg PO) within 1 hour after drug ingestion (may be beneficial even when administered within 3-4 hours after ingestion) b) Plot a nomogram that helps determining the likelihood of serious liver damage (it does not exclude possible toxicity) c) Administer NAC within 8 hours (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 (17 doses) or Loading dose of 150 mg/kg in 5% dextrose IV 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 d) Anticipate allergic reactions while on NAC
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	Deliver immediately
Acute ischemic injury	a) Elevated aminotransferase levels responding to fluid resuscitation b) Associated renal dysfunction & muscle necrosis	Manage the cause of ischemia
Autoimmune	a) Labs: Serum autoantibodies (may be absent) b) Liver biopsy: severe hepatic necrosis with interface hepatitis, plasma cell infiltration and hepatocyte rosettes (confirms diagnosis)	a) Administer 40-60 mg/day of prednisolone b) While on steroids, prepare the patient for transplantation
Budd-Chiari	a) H/o and PE: Abdominal pain, ascites and hepatomegaly b) Liver imaging: CT, doppler USG, venography or magnetic resonance venography (confirms diagnosis)	Transplantation
Drug induced	H/o: Hepatotoxic drug intake	a) Discontinue all possible medications except essential drugs b) Supportive treatment
Malignant infiltration	a) PE: Massive hepatomegaly b) Liver imaging & biopsy: Malignant infiltration	Supportive treatment
Mushroom poisoning	a) H/o: Mushroom intake b) Suspected if no H/o but severe GI symptoms like nausea, vomiting and diarrhea are present	a) Early gastric lavage and activated charcoal administration b) Penicillin G (300,000 1 MU/kg/day) or Silibinin or silymarin 30-40 mg/kg/day IV or PO, 3-4 days (Europe and South America); Milk thistle (North America) c) Fluid resuscitation
Viral	a) Labs: Positive hepatitis virus serology b) Liver biopsy: HSV	a) Hepatitis virus: Supportive treatment b) Positive HBsAg: Possible reactivation, so administer lamivudine or adefovir x 6 months c) HSV and suspected HSV: Acyclovir
Wilson's disease	a) PE: KF ring b) Labs: Serum bilirubin >20g/dL, bilirubin:alkaline phosphatase >2.0, low serum ceruloplasmin, elevated serum & urine copper c) Liver biopsy: Copper deposition	a) Dialysis or hemofiltration or plasmapheresis or plasma exchange b) 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

Complication Specific Management

Complication specific management

Ascites

Cerebral edema & increased ICP

Coagulopathy

Hemodynamic instability

Hepatic encephalopathy

Metabolic disturbances

Renal failure

Standard ascites management

ICP >25 mmHg

+ Bleeding or prior to surgery

*Colloid, dextrose in crystalloid (if hypoglycemic) & 1/2 NS w/ 75 mg/L HCO3 (if acidotic) *Norepinephrine ± vasopressin *Hydrocortisone

Grade

Standard management of acidosis, alkalosis, hypophosphatemia, hypomagnesemia, hypokalemia and hypoglycemia

Standard acute renal failure and hepatorenal syndrome management

SjO2

*Platelet transfusion (if ≤50,000/mm2) *FFP /+ rFVIIa (if INR≥1.5)

I

II

III/IV

<80

>80

*High dependency ward management *2nd hourly monitoring in quiet environment

*ICU management *Stat CT to R/O ICH *Short acting BZD *Lactulose

*ICU management *Intubation & mechanical ventilation *Propofol *Elevate head end to 30° *Quiet environment monitoring of CVP, hemodynamic & renal parameters, serum electrolytes, acid base status & neurological status

20% mannitol

No improvement

Hyperventillation

Worsening

3% NS

Transfer to ICU

Reduce core temperature to 32°-34° (monitor for arrhythmias)

Thiopental 125 mg IV bolus

Improvement or refractory

Transplantation

Do's

General Management

• 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

• Acetaminophen or suspected acetaminophen toxicity:
  • Administer activated charcoal (1g/kg PO) within 1 hour after drug ingestion. May be beneficial even when administered within 3-4 hours after ingestion.
  • Plot a nomogram that helps determining the likelihood of serious liver damage, but does not exclude possible toxicity
  • Administer NAC within 8 hours, 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 (17 doses) or
    • 150 mg/kg in 5% dextrose IV over 15 minutes, then maintenance dose of 50 mg/kg IV over 4 hours and then 100 mg/kg IV over 16 hours
    • Anticipate allergic reactions
• Autoimmune hepatitis:
  • Administer 40-60 mg/day of prednisolone
  • While on steroids, prepare the patient for transplantation
• Budd-Chiari:
  • Rule out malignancy and malignancy associated coagulopathy before transplantation
• Malignant infiltration:
  • Look for carcinoma of breast, small cell carcinoma of lung, lymphoma and melanoma
• Mushroom poisoning:
  • Penicillin G (300,000 1 MU/kg/day)
  • Europe and South America: Silibinin or silymarin; North America: Milk thistle
• Viral:
  • Positive HBsAg: Possible reactivation, so administer lamivudine or adefovir x 6 months
  • Pregnancy and immunocompromised patients: Suspect herpes, so confirm with liver biopsy and administer acyclovir

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 administer protein if ammonia >200 mcg/dL.
• Do not use penicillamine in the treatment of acute liver failure caused by Wilson disease.
• 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.

References

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