327R. Chawla and S. Todi (eds.), ICU Protocols: A stepwise approach, DOI 10.1007/978-81-322-0535-7_41, © Springer India 2012

A 25-year-old male patient presented with recent-onset fever and jaundice, followed by altered sensorium. He had bradycardia, HR 50/min, icterus, and bilateral equal pupils reacting to light. Liver span was one intercostal space with-out splenomegaly. He was unconscious, responding only to painful stimuli. Liver function tests showed total bilirubin of 15 mg/dL, with conjugated fraction of 10 mg/dL, and aspartate transaminase, alanine transaminase, and alkaline phos-phatase were 2,500, 3,000, and 450 IU, respectively. Prothrombin time was more than 1 min over the control. Platelet counts were normal. IgM hepatitis E virus (HEV) antibodies were positive.

Shalimar , M.D., D.M. (*) • S. K. Acharya , M.D. Department of Gastroenterology , All India Institute of Medical Sciences , New Delhi , India e-mail: drshalimar@yahoo.com

41 Acute Liver Failure

Shalimar and Subrat Kumar Acharya

The life of an individual is endangered in acute liver failure (ALF) as a consequence of multiple metabolic and hemodynamic disturbances resulting from severe acute liver injury. This disease carries high morbidity and mortality in the absence of hepatic transplantation.

Step 1: Initiate resuscitation Ensure the maintenance of airway, breathing, and circulation as in any critical • illness, as described in Chap. 78 . Extra precaution needs to be taken while intubating these patients to avoid sudden • increase of intracranial pressure (ICP) and herniation. Proper sedation, anti-edema measures, and experienced personnel are prerequi-• sites for intubation.

328 Shalimar and S.K. Acharya

Step 2: Identify ALF and its causes In a clinical setting, hepatic injury is usually recognized by appearance of • jaundice, and liver failure is recognized by occurrence of encephalopathy, ascites, and coagulopathy. Proper history should be taken regarding medications, rash, needlestick injury, • blood transfusion, previous surgery, and history of jaundice in family members, to identify the cause of fulminant hepatic failure (FHF) (Table 41.1 ). Other causes of fever with encephalopathy such as bacterial sepsis and tropical infec-• tions in endemic areas such as malaria, enteric fever, leptospira, dengue, meningitis, encephalitis, cholangitis, and underlying chronic liver disease should be ruled out. While initial supportive therapy is being given, diagnostic workup should be

sent. These include the following: Complete blood count, blood glucose, blood urea nitrogen, creatinine, electro-• lytes, liver function tests, and prothrombin time Arterial blood gases, arterial ammonia and lactate • Chest X-ray, ECG • Endotracheal aspirate for aerobic culture in intubated patients, blood culture and • urine culture Serology including HBsAg, IgM anti-HBc, IgM anti-HEV, IgM anti-HAV, anti-• HCV, anti-HDV, and anti-HIV Copper studies, autoimmune markers • Bedside ultrasound •

Step 3: Assess prognosis The assessment of the grade of encephalopathy and prognostic indicators should be done, as described in Tables 41.2 and 41.3 . Patients who develop ALF within 7–10 days of the onset of icterus have signi fi cantly higher survival rates than those who develop encephalopathy later. However, this is not a universal fi nding.

Broad categories Infections Metabolic diseases Drugs Toxins ALF of pregnancy Autoimmune hepatitis Acute Budd–Chiari syndrome Shock liver Individual etiological agents Hepatotropic viruses (A to E) Cytomegalovirus, herpes simplex virus Wilson’s disease, galactosemia Paracetamol, isoniazid, rifampicin, sodium valproate Amanita phalloides

Table 41.1 Causes of FHF

32941 Acute Liver Failure

Step 4: Early referral for liver transplant If orthotopic liver transplant (OLT) is available, early referral of such patients • who have adverse prognostic factors to the transplant center is recommended. If the patient is in the transplant center, he or she should be on the transplant list • and workup for that should start before the development of advanced encephal-opathy or other complications of liver failure develop, which are usually fatal (Table 41.4 ). A balanced view regarding chances of spontaneous recovery with supportive • measures, contraindications for transplantation, resources available, and cost consideration needs to be taken judiciously by a multidisciplinary team in each case. Prognostic models such as King’s College criteria and Acute Physiology and • Chronic Health Examination (APACHE) II are helpful in this regard. An APACHE II of more than 15 is associated with increased need for transplantation.

Table 41.2 Clinical stages of hepatic encephalopathy Stage Mental status Neuromuscular function 1 Impaired attention, irritability, depression Tremor, incoordination, apraxia 2 Drowsiness, behavioral changes, memory

impairment, sleep disturbances Asterixis, slowed or slurred speech, ataxia

3 Confusion, disorientation, somnolence, amnesia

Hypoactive re fl exes, nystagmus, clonus, muscular rigidity

4 Stupor and coma Dilated pupils and decerebrate posturing, oculocephalic re fl ex

Table 41.3 Prognostic criteria in ALF predicting high mortality: King’s College and other criteria Nonparacetamol Paracetamol Prothrombin time (PT) >100 s or Plasma pH < 7.30 or Any three of the following: Arterial lactate level >3.5 mmol/L at 4 h or (a) Age <10 or >40 years Arterial lactate level >3.0 mmol/L at 12 h (b) Etiology—non-A, non-B hepatitis Or (c) Drug-induced hepatitis PT > 100 s (INR >6.5) and serum creatinine

>3.4 mg/dL in patients with grade 3–4 encephalopathy

(d) Icterus–encephalopathy interval >7 days (e) PT > 50 s (INR > 3.5) (f) Serum bilirubin > 17.5 mg/dL Clichy criteria (France): (a) Factor V levels <20% of normal in patients <30 years of age (b) Factor V levels <30% of normal in patients >30 years of age Prognostic markers in Indian patients with ALF: 1. Age ³ 40 years Presence of ³ 3 of these factors—90%

mortality 2. Cerebral edema at admission

3. Serum bilirubin ³ 15 mg/dL

4. PT ³ 25 s than normal

330 Shalimar and S.K. Acharya

Step 5 : General supportive measures Correct fl uid status and avoid hypo- or hypervolemia. • Strict aseptic precautions should be practiced while handling catheter and tubes. • Administer supplemental oxygen in case of hypoxemia and avoid hypercapnia. • Avoid hypertension/hypotension. • Manage fever with surface cooling. • Neck should be kept in neutral position. • Minimize external stimuli. • Monitor blood glucose 2 hourly and maintain between 140 and 180 mg%. • Monitor serum electrolytes and correct it. • Nutrition—nasogastric feeding should be started early with gradual increase in • protein supplementation. Strict aseptic precautions should be followed while handling the lines and catheters. •

Step 6: Manage speci fi c problems (a) Cerebral edema and increased ICP

Raise head end 30–45°. • Avoid unnecessary stimulation and movement of the patient—it may induce • overt features of cerebral edema. Identi fi cation of elevated ICP and its management is important because • cerebral edema resulting in brainstem herniation is the commonest cause of death among patients with ALF (Table 41.5 ). Usual recommendation is to keep the ICP below 15 mmHg; however, it is probably more important to maintain the cerebral perfusion pressure (mean arterial pressure minus intracranial pressure) above 50 mmHg. The placement of intracranial transducers is usually avoided in patients with • ALF as it may be associated with life-threatening bleeding and sepsis. Further, such interventions do not improve survival, so it is not practiced widely.

(b) Sepsis is the second major cause of death among ALF. Gram-negative bacteria are the major cause of sepsis in these patients. • Prophylactic parenteral antibiotics using third-generation cephalosporins • may reduce the incidence of sepsis. Fungal infection is also common in this population. Prophylactic fl uconazole, • in selected cases with multiple-site colonization with yeast, may be used. Surveillance cultures should be sent, and high index of suspicion and low • threshold for starting broad-spectrum antibiotics should be practiced.

(c) Renal failure: Both intermittent hemodialysis and continuous renal replacement therapy (CRRT) are equally effective, with later more suitable for unstable patients as it avoids fl uctuation in ICP.

Cerebral edema Sepsis Renal failure Gastrointestinal bleeding

Table 41.4 Causes of death

33141 Acute Liver Failure

(d) Coagulopathy: Prophylactic use of fresh frozen plasma (FFP) is not helpful unless a planned procedure is followed. Once bleeding occurs, only then FFP and platelet transfusion should be given. FFP can precipitate volume overload in these patients, and in selected cases, off-label use of recombinant factor VII may be considered.

(e) Seizures: Prophylactic therapy with phenytoin is not useful. Levetiracetam may be used for the treatment as it does not have hepatotoxicity.

Step 7: Manage speci fi c situation

(a) Paracetamol overdose— N -acetyl cysteine (NAC): 150 mg/kg over 1 h, followed by 12.5 mg/kg/h for 4 h and then 6.25 mg/kg/h for 67 h. NAC has been found to be useful in both acetaminophen and non-acetaminophen-induced ALF.

(b) Special situation—pregnancy – Pregnant women who develop acute viral hepatitis are more likely to develop ALF than

nonpregnant women.

Step 8: Remember that many therapies have doubtful role in the management of ALF and should not be used (Table 41.6 )

Table 41.5 Cerebral edema and raised ICP Symptoms/signs Management Hyperventilation Elevate the head and the trunk 35–40°

Avoid vigorous endotracheal suction Avoid hyperthermia Remove constricting tapes Sedate the patient

Bradycardia 100 mL mannitol (20%) stat followed by 1 g/kg q8 hourly Hypertonic saline

Focal seizures Elective intubation in grades 3–4 encephalopathy Hyperventilation (target PaCO

2 30–32 mmHg) and hypothermia

in selected cases Decerebrate postures Absent pupillary re fl exes

Lactulose l -Ornithine l -aspartate Branched-chain amino acids FFP transfusion in absence of bleeding Prophylactic phenytoin Enteral decontamination Prophylactic hyperventilation for raised intracranial hypertension

Table 41.6 Therapies not useful in ALF

332 Shalimar and S.K. Acharya

Investigate CBC, electrolytes, BUN, creatinine, RBSserum bilirubin, transaminases, PT, CXR, arterial bloodgases, arterial ammonia daily, blood culture endotrachealaspirate in intubated patients, and urine culture

Clinical evaluation and assessment ofgrade of encephalopathy, cerebral edemaand prognostic indicators

Liver transplant available: Earlyreferral—if prognostic models supporthigh mortality at admission

Liver transplant not available/contraindicated: Continue supportive measures

Maintenance of blood sugar, electrolytes, oxygen saturation temperatureCerebral edema: head end elevation, mannitol, intubation in grades 3–4Prophylactic antibiotics: Third-generation cephalosporins, vancomycin, and fluconazole NAC

Resuscitation: A, B, C Admit to ICU.Rule out other causes of fever withencephalopathy

Acute liver failure

Improvement: Continuesupportive therapy

No improvement: Control sepsis(antibiotics as per culturereports), supportive care

Fig. 41.1 A summary of approach to FHF

Suggested Reading

1. Bhatia V, Singhal A, Panda SK, Acharya SK. A 20-year single-center experience with acute liver failure during pregnancy: is the prognosis really worse? Hepatology. 2008;48:1577–85.

The mortality of pregnant patients with ALF is similar to that of nonpregnant women and is independent of the cause or trimester. Pregnancy per se should not be regarded as a poor prognostic factor for a patient with ALF

33341 Acute Liver Failure

2. Acharya SK, Dasarathy S, Kumer TL, Sushma S, Prasanna KS, Tandon A, et al. Fulminant hepatitis in a tropical population: clinical course, cause and early predictors of outcome. Hepatology. 1996;23:1448–55.

The study was conducted prospectively, at a single tertiary care center in India, to document the demographic and clinical characteristics, natural course, and causative pro fi le of patients with FHF as well as to de fi ne simple prognostic markers in these patients. The prognostic model developed in the current study is simple and can be performed at admission .

3. Riegler JL, Lake JR. Fulminant hepatic failure. Med Clin North Am. 1993;77:1057–83. A comprehensive review of the management of fulminant hepatic failure 4. Trey C, Davidson CS. The management of fulminant hepatic failure. In: Popper H, Schaffner F,

editors. Progress in liver failure. New York: Grune and Stratton; 1970. pp. 282–98.