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Hepatic failure
INTENSIVE CARE
Hepatic failure
Causes of acute liver failure
Kevin E J Gunning
Infection Hepatitis A, B, C, E, seronegative, cytomegalovirus, herpes simplex virus, Epstein–Barr virus, varicella Drugs Paracetamol, isoniazid, rifampicin, non-steroidal antiinflammatory drugs, halothane, Ecstasy, phenytoin, ketoconazole, monoamine oxidase inhibitors Metabolic Wilson’s disease, Reye’s syndrome Cardiovascular Budd–Chiari syndrome, ischaemic hepatitis Miscellaneous Acute fatty liver of pregnancy, HELLP syndrome, autoimmune hepatitis, lymphoma, Amanita phalloides, herbal medicines
Acute liver failure is a rare, multisystem disease characterized by a rapid deterioration in liver function and the development of a coagulopathy and encephalopathy in a patient with previously normal liver function. The terms hyperacute, acute and subacute are used to define the onset of encephalopathy in 7 days, 7–28 days and more than 28 days, respectively. Patients with pre-existing liver disease who decompensate are not included in this definition. 1
Aetiology In the UK, the most common cause of liver failure is paracetamol (acetaminophen) overdose, but this has declined with the restriction in the number of tablets that can be purchased at one time. Worldwide, the most common cause is viral hepatitis. Idiosyncratic drug reactions are also a significant cause (Figure 1).
to the support of the organ systems involved, allowing the liver time to regenerate. Patients may deteriorate rapidly and if they have grade I or II encephalopathy (see below) they should be transferred to a liver centre, after resuscitation and stabilization, to allow an early decision about the need for liver transplantation to be made. Patients with grade II encephalopathy should be intubated and ventilated before transfer. The cardiovascular changes are similar to those in sepsis, with a high cardiac output and a low peripheral vascular resistance. Patients require initial resuscitation, with either crystalloid or colloid solution. There may be profound hypotension, and inotropic support with norepinephrine to maintain a mean arterial pressure of 60 mm Hg is commonly required. Terlipressin should not be used because there is evidence that it may increase cerebral blood flow. Some centres use N-acetylcysteine in non-paracetamol-induced acute liver failure, with the aim of increasing oxygen delivery, but there are doubts about its efficacy, and the results of a multicentre trial are awaited. Cardiovascular monitoring with a PiCCO, LiDCO, or pulmonary artery catheter should be used to guide fluid resuscitation and the use of inotropes. Renal failure is common, especially in paracetamol overdose due to a direct nephrotoxic effect. Continuous veno-venous haemofiltration should be started early using a lactate-free replacement fluid, because the failing liver will not clear lactate. Haemofiltration may be used to correct hyponatraemia, acidosis and the removal of fluid in the management of cerebral oedema.
Diagnosis and investigations A history should be obtained from the patient or their relatives, including information about drug ingestion, exposure to toxins, or travel. The patient may be jaundiced and the liver is enlarged in early viral hepatitis or Budd–Chiari syndrome. Signs of chronic liver disease, such as clubbing and spider naevi, are not present. Initial investigations should include estimation of the prothrombin time, glucose, blood gas analysis, creatinine and lactate. Plasma paracetamol levels, hepatitis serology and caeruloplasmin should be measured and urinary copper tested for Wilson’s disease. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are markedly elevated, reflecting hepatocellular damage, but do not correlate with the outcome. Hepatic Doppler ultrasound should be performed to assess the patency of the portal and hepatic veins. Management Acetaminophen overdose results in the accumulation of the hepatotoxic metabolite N-acetyl-p-benzoquinone imine, which is normally inactivated by conjugation with glutathione. N-acetylcysteine should be given to patients who are suspected of having taken a paracetamol overdose, according to the standard nomogram. Apart from N-acetylcysteine, there are no specific treatments for patients with acute liver failure and management is directed
Encephalopathy Encephalopathy is graded from I to IV (Figure 2). It is associated with cerebral oedema and raised intracranial pressure and is the cause of death in 35% of cases. Cerebral oedema is present in 35% of patients with grade III encephalopathy and over 75% of patients in grade IV coma. Current theories include the loss of autoregulation, resulting in cerebral hyperaemia, and altered ammonia metabolism leading to astrocyte swelling. To control intracranial pressure:
Kevin E J Gunning is Consultant in Anaesthesia and Intensive Care Medicine at Addenbrooke’s Hospital, Cambridge, UK. He trained in anaesthesia in London and Geneva. His interests include training in intensive care and the intensive care management of patients with liver disease.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 7:4
119
© 2006 Elsevier Ltd
INTENSIVE CARE
• 10% glucose to correct hypoglycaemia. Liver transplantation is the only definitive treatment for acute liver failure and over 50% of patients undergo transplantation. Features that have been shown to identify patients with a poor prognosis without transplantation include: • grade III or IV coma on presentation • pH less than 7.3 • prothrombin time over 100 s • idiosyncratic drug injury, seronegative hepatitis, Wilson’s disease, Budd–Chiari syndrome. As there is no definitive treatment for liver failure, there has been considerable research into the development of an artificial liver. Trials of systems using extracorporeal perfusion of blood through columns of porcine hepatocytes, or dialysis against an albumin-coated membrane have been undertaken. The studies are small and no phase III trials have confirmed the efficacy of these treatments.
Grades of encephalopathy Grade I Altered mood, impaired concentration and psychomotor function, rousable Grade II Drowsy, disorientation, able to talk Grade III Very drowsy, confusion, agitation, aggression Grade IV Coma, may respond to painful stimuli 2
• nurse the patient at 30° head up • ensure minimal nursing interventions • sedate with propofol infusion and paralyse if necessary • maintain PaCO2 at 4–4.5 kPa • maintain temperature below 37°C • treat seizures with phenytoin. Mild hypothermia (32–33°C) and 5% hypertonic saline may also lower intracranial pressure and are being investigated. Prompt detection of episodes of raised intracranial pressure is important to avoid cerebral herniation and permanent brain damage. A spike in the arterial pressure is a sign of a rise in intracranial pressure and should be treated immediately. Pupillary signs occur late and should not be relied on. CT is not a sensitive indicator of cerebral oedema in this setting. A rise in intracranial pressure should be treated with: • mannitol 20%, 0.5 g/kg i.v. (repeat boluses may be given if the serum osmolality is less than 320 mOsmol/litre) • thiopental, 50 mg bolus i.v., or i.v. infusion of 50 mg/hour. Invasive intracranial pressure monitoring is used in some centres, but carries the risk of bleeding and infection. If it is used, the cerebral perfusion pressure should be maintained above 60 mm Hg and intracranial pressure below 20–25 mm Hg. There are no trials that show an improved outcome with its use.
Prognosis The prognosis for spontaneous recovery has increased from 15% to 40% with improvements in patient management and over 65% survival after transplantation. The main causes of death are refractory hypotension (70%) and cerebral herniation. Acute-on-chronic liver disease Patients with chronic liver disease due to cirrhosis who develop hepatic failure present with a different set of clinical features. Encephalopathy is present, but in contrast to acute liver failure is not associated with cerebral oedema. Portal hypertension leads to oesophageal varices and portal gastropathy. Variceal bleeding or infections, such as spontaneous bacterial peritonitis commonly precipitate acute-on-chronic hepatic failure. The prognosis for patients with decompensated chronic liver disease who are admitted to intensive care and require inotropes and develop renal failure is very poor.
Coagulopathy Coagulopathy is a major feature of acute liver failure because the liver synthesizes all the clotting factors apart from factor VIII. Sepsis, reduced protein C and antithrombin III levels contribute to low-grade disseminated intravascular coagulation. Because of the short half-life of the coagulation factors, the prothrombin time is a useful indicator of the progression of the disease. Therefore in the absence of active bleeding, coagulation factors should not be given except if invasive procedures or transplantation are planned. The platelet count should be maintained above 50 × 109/litre. Recombinant factor VIIa may be effective in the temporary correction of the coagulopathy. Other measures The following measures should also be instituted: • H2 antagonists, ranitidine, 50 mg 8 hourly i.v. • antibiotic prophylaxis with cefotaxime, 1 g 8 hourly i.v., fluconazole, 100 mg/day i.v. • enteral or parenteral feeding
ANAESTHESIA AND INTENSIVE CARE MEDICINE 7:4
FURTHER READING Jalan R. Acute liver failure: current management and future prospects. J Hepatol 2005; 42: S115–23. O’Grady J. Acute liver failure. Postgrad Med J 2005; 81: 148–54. Polson J, Lee W M. AASLD Position paper: The management of acute liver failure. Hepatology 2004; 41: 1179–97.
120
© 2006 Elsevier Ltd
Hepatic failure
Causes of acute liver failure
Kevin E J Gunning
Infection Hepatitis A, B, C, E, seronegative, cytomegalovirus, herpes simplex virus, Epstein–Barr virus, varicella Drugs Paracetamol, isoniazid, rifampicin, non-steroidal antiinflammatory drugs, halothane, Ecstasy, phenytoin, ketoconazole, monoamine oxidase inhibitors Metabolic Wilson’s disease, Reye’s syndrome Cardiovascular Budd–Chiari syndrome, ischaemic hepatitis Miscellaneous Acute fatty liver of pregnancy, HELLP syndrome, autoimmune hepatitis, lymphoma, Amanita phalloides, herbal medicines
Acute liver failure is a rare, multisystem disease characterized by a rapid deterioration in liver function and the development of a coagulopathy and encephalopathy in a patient with previously normal liver function. The terms hyperacute, acute and subacute are used to define the onset of encephalopathy in 7 days, 7–28 days and more than 28 days, respectively. Patients with pre-existing liver disease who decompensate are not included in this definition. 1
Aetiology In the UK, the most common cause of liver failure is paracetamol (acetaminophen) overdose, but this has declined with the restriction in the number of tablets that can be purchased at one time. Worldwide, the most common cause is viral hepatitis. Idiosyncratic drug reactions are also a significant cause (Figure 1).
to the support of the organ systems involved, allowing the liver time to regenerate. Patients may deteriorate rapidly and if they have grade I or II encephalopathy (see below) they should be transferred to a liver centre, after resuscitation and stabilization, to allow an early decision about the need for liver transplantation to be made. Patients with grade II encephalopathy should be intubated and ventilated before transfer. The cardiovascular changes are similar to those in sepsis, with a high cardiac output and a low peripheral vascular resistance. Patients require initial resuscitation, with either crystalloid or colloid solution. There may be profound hypotension, and inotropic support with norepinephrine to maintain a mean arterial pressure of 60 mm Hg is commonly required. Terlipressin should not be used because there is evidence that it may increase cerebral blood flow. Some centres use N-acetylcysteine in non-paracetamol-induced acute liver failure, with the aim of increasing oxygen delivery, but there are doubts about its efficacy, and the results of a multicentre trial are awaited. Cardiovascular monitoring with a PiCCO, LiDCO, or pulmonary artery catheter should be used to guide fluid resuscitation and the use of inotropes. Renal failure is common, especially in paracetamol overdose due to a direct nephrotoxic effect. Continuous veno-venous haemofiltration should be started early using a lactate-free replacement fluid, because the failing liver will not clear lactate. Haemofiltration may be used to correct hyponatraemia, acidosis and the removal of fluid in the management of cerebral oedema.
Diagnosis and investigations A history should be obtained from the patient or their relatives, including information about drug ingestion, exposure to toxins, or travel. The patient may be jaundiced and the liver is enlarged in early viral hepatitis or Budd–Chiari syndrome. Signs of chronic liver disease, such as clubbing and spider naevi, are not present. Initial investigations should include estimation of the prothrombin time, glucose, blood gas analysis, creatinine and lactate. Plasma paracetamol levels, hepatitis serology and caeruloplasmin should be measured and urinary copper tested for Wilson’s disease. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are markedly elevated, reflecting hepatocellular damage, but do not correlate with the outcome. Hepatic Doppler ultrasound should be performed to assess the patency of the portal and hepatic veins. Management Acetaminophen overdose results in the accumulation of the hepatotoxic metabolite N-acetyl-p-benzoquinone imine, which is normally inactivated by conjugation with glutathione. N-acetylcysteine should be given to patients who are suspected of having taken a paracetamol overdose, according to the standard nomogram. Apart from N-acetylcysteine, there are no specific treatments for patients with acute liver failure and management is directed
Encephalopathy Encephalopathy is graded from I to IV (Figure 2). It is associated with cerebral oedema and raised intracranial pressure and is the cause of death in 35% of cases. Cerebral oedema is present in 35% of patients with grade III encephalopathy and over 75% of patients in grade IV coma. Current theories include the loss of autoregulation, resulting in cerebral hyperaemia, and altered ammonia metabolism leading to astrocyte swelling. To control intracranial pressure:
Kevin E J Gunning is Consultant in Anaesthesia and Intensive Care Medicine at Addenbrooke’s Hospital, Cambridge, UK. He trained in anaesthesia in London and Geneva. His interests include training in intensive care and the intensive care management of patients with liver disease.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 7:4
119
© 2006 Elsevier Ltd
INTENSIVE CARE
• 10% glucose to correct hypoglycaemia. Liver transplantation is the only definitive treatment for acute liver failure and over 50% of patients undergo transplantation. Features that have been shown to identify patients with a poor prognosis without transplantation include: • grade III or IV coma on presentation • pH less than 7.3 • prothrombin time over 100 s • idiosyncratic drug injury, seronegative hepatitis, Wilson’s disease, Budd–Chiari syndrome. As there is no definitive treatment for liver failure, there has been considerable research into the development of an artificial liver. Trials of systems using extracorporeal perfusion of blood through columns of porcine hepatocytes, or dialysis against an albumin-coated membrane have been undertaken. The studies are small and no phase III trials have confirmed the efficacy of these treatments.
Grades of encephalopathy Grade I Altered mood, impaired concentration and psychomotor function, rousable Grade II Drowsy, disorientation, able to talk Grade III Very drowsy, confusion, agitation, aggression Grade IV Coma, may respond to painful stimuli 2
• nurse the patient at 30° head up • ensure minimal nursing interventions • sedate with propofol infusion and paralyse if necessary • maintain PaCO2 at 4–4.5 kPa • maintain temperature below 37°C • treat seizures with phenytoin. Mild hypothermia (32–33°C) and 5% hypertonic saline may also lower intracranial pressure and are being investigated. Prompt detection of episodes of raised intracranial pressure is important to avoid cerebral herniation and permanent brain damage. A spike in the arterial pressure is a sign of a rise in intracranial pressure and should be treated immediately. Pupillary signs occur late and should not be relied on. CT is not a sensitive indicator of cerebral oedema in this setting. A rise in intracranial pressure should be treated with: • mannitol 20%, 0.5 g/kg i.v. (repeat boluses may be given if the serum osmolality is less than 320 mOsmol/litre) • thiopental, 50 mg bolus i.v., or i.v. infusion of 50 mg/hour. Invasive intracranial pressure monitoring is used in some centres, but carries the risk of bleeding and infection. If it is used, the cerebral perfusion pressure should be maintained above 60 mm Hg and intracranial pressure below 20–25 mm Hg. There are no trials that show an improved outcome with its use.
Prognosis The prognosis for spontaneous recovery has increased from 15% to 40% with improvements in patient management and over 65% survival after transplantation. The main causes of death are refractory hypotension (70%) and cerebral herniation. Acute-on-chronic liver disease Patients with chronic liver disease due to cirrhosis who develop hepatic failure present with a different set of clinical features. Encephalopathy is present, but in contrast to acute liver failure is not associated with cerebral oedema. Portal hypertension leads to oesophageal varices and portal gastropathy. Variceal bleeding or infections, such as spontaneous bacterial peritonitis commonly precipitate acute-on-chronic hepatic failure. The prognosis for patients with decompensated chronic liver disease who are admitted to intensive care and require inotropes and develop renal failure is very poor.
Coagulopathy Coagulopathy is a major feature of acute liver failure because the liver synthesizes all the clotting factors apart from factor VIII. Sepsis, reduced protein C and antithrombin III levels contribute to low-grade disseminated intravascular coagulation. Because of the short half-life of the coagulation factors, the prothrombin time is a useful indicator of the progression of the disease. Therefore in the absence of active bleeding, coagulation factors should not be given except if invasive procedures or transplantation are planned. The platelet count should be maintained above 50 × 109/litre. Recombinant factor VIIa may be effective in the temporary correction of the coagulopathy. Other measures The following measures should also be instituted: • H2 antagonists, ranitidine, 50 mg 8 hourly i.v. • antibiotic prophylaxis with cefotaxime, 1 g 8 hourly i.v., fluconazole, 100 mg/day i.v. • enteral or parenteral feeding
ANAESTHESIA AND INTENSIVE CARE MEDICINE 7:4
FURTHER READING Jalan R. Acute liver failure: current management and future prospects. J Hepatol 2005; 42: S115–23. O’Grady J. Acute liver failure. Postgrad Med J 2005; 81: 148–54. Polson J, Lee W M. AASLD Position paper: The management of acute liver failure. Hepatology 2004; 41: 1179–97.
120
© 2006 Elsevier Ltd