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Management of acute liver failure

Created: 11/9/2008
Updated: 12/9/2008

Management of acute liver failure

Christopher J Loew FRCA MRCP DICM
Advanced Trainee in Intensive Care Medicine & Anaesthesia
Oxford Radcliffe Hospitals NHS Trust

Focus on aetiology and definition of acute liver failure

Acute liver failure (ALF) results from an abrupt loss of hepatic metabolic and synthetic function and leads to encephalopathy and potentially multi-organ dysfunction. Aetiologies include autoimmune and metabolic diseases, infectious agents and hepatotoxins. Worldwide, infectious hepatitis (A, B and E) is the most common cause. In Western Europe and the USA, ALF is most frequently caused by paracetamol intoxication.

Depending on the jaundice-to-encephalopathy time, ALF can be subdivided into:

• hyperacute (onset <1 week)
• acute (onset 8-28 days)
• subacute liver failure (29 days to 12 weeks).

This classification has prognostic implications and can give clues about the aetiology of ALF. In the UK, hyperacute liver failure is almost always caused by paracetamol toxicity and has, compared with all other causes, the highest rates of spontaneous survival (57%) and the lowest rate of transplantation (7-9%). Subacute liver failure has a much poorer prognosis.

Once the diagnosis of ALF has been made and either the history and/or blood results are suggestive of a paracetamol overdose (POD), treatment should be commenced immediately and if the patient fulfils the criteria outlined in Table 1, they should be treated in a specialist liver ICU.

Table 1. Criteria for referral to a specialist liver centre

   Day 2 Day 3  Day 4  
Conscious level    Encephalopathy  Encephalopathy  Encephalopathy
 INR  >3.0  >4.5  Any increase since day 2
 Creatinine (μmol/L)  >200  >200  >250
 Arterial pH  <7.3  <7.3  --
 Blood sugar  Hypoglycaemia  --  --


Specific management of paracetamol-induced ALF

Focus on N-acetylcysteine

Intravenous N-acetylcysteine (NAC) should be administered as soon as possible. There is confirmed benefit if given early (<24 hours after POD), but even after 48-72 hours it may reduce the incidence of cerebral complications and mortality. NAC should be continued until there is firm evidence of improved hepatic function or the patient has been transplanted or died.

Focus on hepatic encephalopathy and cerebral oedema

In deeper levels of coma, hepatic encephalopathy may be associated with cerebral oedema and raised intracranial pressure (ICP). The pathogenesis is not yet clear, but hyperammonaemia is thought to be a central factor. Ammonia, produced by microorganisms in the gut, bypasses hepatic metabolism and is detoxified in astrocytes to osmotically active glutamine. This, in turn, may contribute to the development of cerebral oedema.

Currently, there are insufficient data to recommend the use of lactulose or non-absorbable antibiotics (e.g. neomycin) in ALF in order to try and prevent encephalopathy by reducing the synthesis of ammonia in the gut. Treatment of established cerebral oedema and raised ICP should focus on the maintenance of cerebral perfusion pressure guided by invasive monitoring of ICP. Patients should be ventilated, aiming for normoxia and normocapnia. At the same time, hypotension, hypoglycaemia and hyperthermia should be avoided.

Focus on sedation and analgesia

Sedatives and opiates should be used with great care in patients with ALF. Due to impaired protein binding capacity and impaired hepatic metabolism, they may be very susceptible to small doses. This may aggravate the clinical picture of encephalopathy and reduce its usefulness as a marker of severity and disease progression.

At higher levels of encephalopathy, however, and especially in the presence of raised ICP, adequate analgesia and sedation may be necessary to prevent spikes in ICP due to external stimuli (e.g. endotracheal intubation and suctioning). Short-acting agents in reduced doses should be used.

Focus on fluid management and nutrition

ALF is often associated with hypovolaemia, and aggressive fluid resuscitation may be required. Excessive use of dextrose-containing fluids should be avoided, as they may contribute to hyponatraemia and cerebral oedema. Noradrenaline may be required. ALF is characterised by a catabolic state, and enteral nutrition should be administered where possible.

Focus on correction of coagulopathy

Despite, often severe, coagulopathies, clinically significant bleeding is uncommon. Fresh frozen plasma (FFP) should only be given prior to the placement of invasive devices or surgery or in the presence of an uncontrollable bleed. Administration of FFP will obscure the trend of the prothrombin time (PT) as a prognostic marker.

Focus on infection prophylaxis

Patients with ALF are prone to infections with Gram-positive cocci, enteric Gram-negative bacilli and fungi (mainly Candida) but often do not exhibit signs of infection. Patients listed for liver transplantation should receive prophylactic antibiotics, as an infection will result in delisting and immunosuppression will follow transplantation. However, this practice is not evidence based.

Focus on renal management

70% of patients with POD-associated ALF will develop renal failure due to acute tubular necrosis caused by direct nephrotoxic effects of paracetamol. In the acute setting, renal replacement therapy is often required, but the vast majority of patients make a good recovery.

Focus on listing for transplant

The only therapy of confirmed benefit in patients with advanced ALF is liver transplantation. The King’s College criteria are commonly used to select patients who will benefit from urgent liver transplantation. Patients with paracetamol hepatotoxicity will be considered for liver transplantation if they fulfil the following criteria:

  • arterial pH <7.30 or 7.25 if NAC has been administered

or all three of the following:

  • PT >100 seconds 
  • Creatinine >300 μmol/L 
  • Grade III encephalopathy.

Contraindications to liver transplantation include irreversible brain damage, accelerating inotrope requirements, uncontrolled sepsis and severe respiratory failure. In the UK, the majority of patients will be transplanted within 48 hours of registration.

Key Learning Points

• The management of acute liver failure is complex.
• It is important to recognise acute liver failure early and undertake proper classification and accurately determine aetiology.
• Early treatment with NAC has an important role in the management of acute liver failure secondary to paracetamol hepatotoxicity.
• Early involvement of liver ICU specialists is of vital importance in the management of acute liver failure.

Key References

O'Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993; 342(8866): 273-5.

O'Grady J. Modern management of acute liver failure. Clin Liver Dis 2007; 11(2): 291-303.

Lai WK, Murphy N. Management of acute liver failure. Contin Educ Anaesth Crit Care Pain 2004; 4(2): 40-3.

Keays R et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991; 303(6809): 1026-9.

Stravitz RT et al. Intensive care of patients with acute liver failure: recommendations of the US Acute Liver Failure Study Group. Crit Care Med 2007; 35(11): 2498-508.

Rolando N, Philpott-Howard J, Williams J. Bacterial and fungal infection in acute liver failure. Semin Liver Dis 1996; 16(4): 389-402.

Bernal W, Wendon J. Acute liver failure. Curr Opin Anaesthesiol 2000; 13(2): 113-8.

O'Grady JG et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97(2): 439-45.

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