Fulminant Hepatic Failure - development of hepatic encephalopathy within 8 weeks of onset of illness. Acute liver failure with hepatic encephalopathy in patients with no history or stigmata of chronic liver disease (presumed to have normally functioning livers prior to the onset of the illness).
Acute Liver Failure - acute hepatic disease associated with altered mental status (hepatic encephalopathy) and coagulopathy.
Etiologies - ( viral,toxic, metabolic, autoimmune, ischemic, neoplastic )
- Viral hepatitis ( A,B,C,D,E,F,G, herpes, CMV, EB )
- Drug -related liver injury (Acetaminophen, idiosyncratic, INH, anticonvulsants)
- Toxins (EtOH, Amanita phalloides, CCl4, halothane, DPH)
- Vascular events (ischemia, hypotension, veno-occlusive disease, hyperthermia)
-Miscellaneous (Wilson’s, fatty liver of pregnancy, Reye’s, malignant infiltration)
Diagnosis
- Initial nonspecific prodrome (nausea, malaise)
- Jaundice or icteric phase
- AMS and coma
- Mistaken for drug overdose, gram negative sepsis
-Prolonged PT
- High aminotransferases
- Low glucose
- Respiratory alkalosis
coagulopathy - any patient with coagulopathy may die and should be admitted to ICU
Complications
common complications in patients with FHF include encephalopathy, cerebral edema, cardiovascular instability, hypoglycemia, infection, bleeding, and renal failure
complications of advanced cirrhosis also include spontaneous bacterial peritonitis, variceal hemorrhage, and hypoxemia
Encephalopathy
- Hepatic encephalopathy is defined as reversible neuropsychiatric dysfunction associated with acute or chronic liver failure
- Initial agitation, hyperkinesis, and delusions
- Rapid progression to coma
Grade I - Diagnosis in retrospect, mild personality changes, fine tremor
Grade II - mild obtundation, drowsiness, lethargy, tremor ++, asterixis
Grade III - stupor, somnolence, arousal to voice, tremor if cooperative, hyperreflexia
Grade IV - coma, response to pain (A) or no response (B), posturing
Pathopysiology of HE is unknown, but is believed to be secondary to endogenous neuro-inhibitory benzodiazepine- like substances and ammonia. Flumazenil may improve coma grade temporarily
Must also consider drug induced causes for obtundation (due to decreased metabolism), hypoglycemia, subdural hematoma, meningitis, subclinical status epilepticus, hypoxemia, Wernicke’s encephalopathy
Precipitating factors include GI bleed, SBP, sepsis, Drugs, dietary protein load, alkalosis, diuretics, dehydration, constipation, azotemia
Cerebral Edema
- Cerebral edema in 75 % of grade IV; leading cause of death; secondary to loss of cell membrane and BBB integrity; Cushing response, increased tone, posturing, and brain stem respiratory patterns are late signs
- CT scans unreliable but exclude bleed (only 1/3 demonstrate edema)
- Mannitol useful
- Elevation of HOB may be harmful by diminishing CPP
- Dexamethasone and hyperventilation not useful
Coagulopathy
- Decreased II, V, VII, IX, X
- Decreased PLT
- FFP of no value in absence of bleeding
Renal and CV
- Distributive hemodynamics
- Hypotension, decreased SVR
- Hepatorenal syndrome
Oxygen Transport and Delivery
- Severe peripheral shunting may result from peripheral PLT plugs, interstitial edema, abnormal vasomotor tone
-Diminished O2 extraction
Metabolic Changes
- Hypoglycemia is common (defective gluconeogenesis, decreased glycogen stores)
- D10W may be required
- Hypokalemia
- Hyponatremia
- Hypophosphatemia
Infection
- Risks - decreased level of consciousness, invasive catheters, immunocompromise (diminished opsonic activity, PMN function, phagocytopsis, impaired CMI, humoral immunity), portosystemic collaterals allow bacteria to bypass the hepatic reticuloendothelial system
- Bacteremia, fungemia common
- GPC (Staph aureus and epidermidis, Strep), GNR
no benefit from prophylactic ATB but empiric broad spectrum antibiotic therapy is indicated if signs of sepsis
One prospective study demonstrated an 80% infection rate in patients with FHF. Pneumonia and UTI were the most common sites of infection, bacteremia was documented in 26% of patients.
Pathogenesis
- Endotoxemia, TNF, prostaglandins
Therapy
- Elucidate the cause (APAP or mushroom poisoning)
- Measure APAP, viral serology, PT
- Follow glucose and give D10W
- H2 blockers
- Airway, ventilator support
- Hemodynamic monitoring and support
Management of FHF
- ICU admission for anyone with a coagulopathy
Airway protection- ETT at grade III; high risk for aspiration
Treatment of encephalopathy with lactulose or non-absorbable antibiotics
Careful serial neurologic exams +- ICP monitoring
Aggressive treatment of bleeding with blood products ( but correction of coagulopathy only if bleeding) - FFP only indicated for bleeding or prior to invasive line insertions, Vt K
Treatment of hypotension with volume resuscitation, vassopressors ( CVP, arterial line, NG, Foley) consider GI bleed, hypovolemia, septic shock as causes of hypotension
Empirical antibiotic therapy if signs of sepsis (broad spectrum ATB, consider fungal sepsis)
Nutrition including vitamin replacement- consider branched-chain amino acids
Avoidance of hypoglycemia- hypoglycemia occurs in 40 % - start on D10W, do regular accuchecks
Renal failure - r/o hypovolemia; CAVH-D or CVVH-D
Drug metabolism - reduced protein binding, hepatic metabolism, and co-existing renal failure mean that drugs metabolized by the liver or eliminated by the kidneys will need to have dosage adjustments
Orthotopic liver transplantation is definitive therapy for FHF
Hepatic Encephalopathy
avoid aggravating factors ( hypoxia, hypotension, sepsis, hypoglycemia, hemorrhage, drugs, fluid and electrolyte imbalances )
Remove/control precipitating factors
dietary protein restriction
Reduce colon-derived nitrogenous substances
- Lactulose titrated to 3 - 4 bm/day
- Metronidazole
- Neomycin (caution with renal failure)
Cerebral edema
- >50 % if late stage III or IV
- ICP monitoring by extradural transducers (no RCT - increased duration by 50 hrs)
Complications of bleeding and infection
improved anaesthetic Mx
routine use of ICP monitors is controversial
- Mannitol- useful if high clinical suspicion of increased ICP or herniation syndrome; beware of neprotoxicity, monitor osmolarity
Barbiturates - no RCT regarding efficacy
Intubate with careful rapid sequence protocol using ICP precautions
- Hyperventilation - prophylactic use not beneficial, useful as a temporizing measure when signs of herniation develop
- Positioning
- Charcoal hemoperfusion - no benefit in RCT
- Steroids - no benefit
Infection
- Bacterial and fungal
-Gram pos and neg
- Fever and leukocytosis often absent - aggressive daily surveillance
- ? Prophylactic neomycin, nystatin,or norfloxacin plus nystatin
Coagulopathy
decreased hepatic coagulation factors, thrombocytopenia, DIC, fibrinolysis
Vitamin K
H2 antagonists to increase gastric pH
- Prophylactic FFP not beneficial in RCT
- Limit FFP to bleeding or prior to invasive procedure
- Can worsen cerebral edema (nitrogen, salt, water)
- ? plasma exchange
Hemodynamics/ Circulatory Impairment
- Low SVR, high CO
- Microcirculatory shunting with decreased O2 consumption/extraction
- Lactic acidosis
- PGI and NAC increase extraction
Chronic Liver Disease
Etiologies
Cirrhosis
Chronic active hepatitis
Hepatic vein thrombosis (Budd-Chiari syndrome)
Complications
Hepatic encephalopathy
Variceal hemorrhage
Spontaneous bacterial peritonitis
Hepato-renal syndrome
Variceal hemorrhage
30 % have bleeding originating from another GI source, thus must do G-scope
15% bleed from gastric varices ( prominent gastric varices without esophageal varices suggests splenic vein thrombosis
spontaneous cessation of bleeding is common, but rebleeding is the rule if definitive therapy is not taken
Airway protection - low threshold to intubate
Hemodynamic resuscitation including PRBC’s - large bore iv lines/ central line
Correction of coagulopathies
Octreotide - synthetic analog of somatostatin ; superior to vassopressin + NTG
Endoscopy to confirm diagnosis and treat with banding or sclerotherapy
Blakemore tube as temporizing measure if the above is unsuccessful
Definitive therapies - TIPS, Surgical porto-systemic shunt, liver transplant
Beta-blockers to decrease long-term incidence of rebleeding
Spontaneous Bacterial Peritonitis
An infection of pre-existing cirrhotic ascites without an apparent perforated viscus.
50% in-hospital mortality rate
Gram negative aerobic bacilli ( E coli, Klebsiella, streptococci )
Diagnosis by paracentesis ( WBC > 250/ml, pH , 7.35, lactate > 25 mg/dL, positive cultures)
Must consider appendicitis, cholecytitis, diverticulitis, perforated viscus
Cefotaxime 2 gm iv q6h
References
1) Fulminant and subfulminant liver failure : Definitions and causes. Seminars in liver disease.
1986;6:97-106
2) Acute liver failure. NEJM 1993;329:1862-1872
3) Hepatic encephalopathy and cerebral edema. Seminars in liver disease. 1986;6:107-118
4) Acute liver failure. Lancet 1995;345:163-169.
5) Pulmonary complications in acute liver failure : analysis of serial radiographs in 100 consecutive patients. Clin Radiol. 1978;29:363-369
6) Determining the prognosis in patients with fulminant hepatic failure: when you absolutely, positively, have to know the answer. Hepatology. 1995;21:879-882
7) Hemostasis in liver transplantation. Gastroenterology. 1989;97:488-501
8) Hemostasis and fibrinolysis in severe liver failure and their relation to hemorrhage.
Hepatology. 1986;6:79-86
9) Acute hepatic failure: the emerging role of orthotopic liver transplantation.
Mayo Clinic Proceedings 1989;64:424-428
10) Complications of intracranial pressure monitoring in fulminant hepatic failure.
Lancet 1993;341:157-158
11) Contolled trials of charcoal hemoperfusion and prognostic factors in fulminant liver disease.
Gastroenterology 1988;94:1186-92
12) Prognosis of patients with cirrhosis and chronic liver disease admitted to the MICU. Crit Care Med 1988;16:671-678
13) The lung in liver disease. Clin Chest Med 1996;#17, vol1
14 ) The role of transjugular liver biopsy in fulminant liver failure: Relation to other prognostic indicators. Hepatology 1993; 18:1370-1374
15) Rolando N, harvey F, et al; Prospective study of bacterial infection in acute liver failure: An analysis of 50 patients. Hepatology 1990, 11: 49
Patrick Melanson, MD, FRCPC