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Hepatic failure
INTENSIVE CARE
Hepatic failure
Learning objectives
Norma McAvoy After reading this article you should be able to: C recognise the differences in presentation of acute and chronic liver failure C investigate and manage patients with liver disease in the intensive care unit C understand why liver disease results in the dysfunction of multiple organ systems
Euan Thomson Elizabeth S Wilson
Abstract The incidence of liver disease is increasing in the UK, attributable to a surge in excessive alcohol consumption and obesity. It is therefore not surprising that intensive care units are managing more patients with chronic liver disease. These individuals are often malnourished and can rapidly progress to multi-organ failure, requiring prolonged spells of organ support. However the spectrum of liver dysfunction encountered in the critical care setting is quite diverse and includes patients with: acute liver failure decompensation of chronic liver disease and associated complications impaired liver function secondary to severe systemic illness and its treatment. In this article we describe the aetiology, investigation, management and prognosis of patients presenting to critical care with severe liver impairment. Transplantation has radically modified the outcome for many patients and early specialist referral should be considered.
Chronic liver failure In contrast, chronic liver disease arises when the normal cytoarchitecture of the liver is gradually destroyed. Normal hepatic tissue is progressively replaced by scar tissue (cirrhosis). This results not only in gradual diminution of normal metabolic and synthetic hepatic function but also alteration in liver blood flow and development of portal hypertension. Liver failure is said to be present when either ascites or encephalopathy is present. The signs and symptoms of chronic liver disease reflect a slow progressive deterioration in liver function. They include fatigue, itch, weight loss, progressive jaundice, ascites, encephalopathy and stigmata of chronic liver disease (e.g. spider naevi). However, even patients with advanced chronic liver disease may be relatively asymptomatic. These patients often come to the attention of critical care following an acute worsening of symptoms precipitated by an additional insult, for example variceal haemorrhage, systemic infection or spontaneous bacterial peritonitis.
Keywords Encephalopathy; liver failure; management; pathophysiology; prognosis; transplant criteria
Acute liver failure
Liver dysfunction in critical illness
Liver failure can develop rapidly in patients with previously normal hepatic function. The predominant mechanism of action is destruction of hepatocytes. Previously the term ‘fulminant hepatic failure’ was attributed to hepatic failure with encephalopathy presenting within 8 weeks of first symptoms of liver injury, in patients without pre-existing liver disease. More recently the terms hyperacute, acute and subacute liver failure have gained widespread use, reflecting time from development of jaundice to encephalopathy of 0e7 days, 8e28 days and 4e12 weeks respectively. Symptoms of acute liver failure are often initially mild and non-specific (e.g. abdominal pain and nausea), but rapidly progress to include jaundice, coagulopathy and encephalopathy.
Critically ill patients can develop liver dysfunction in the absence of primary hepatic disease. Common causes include ischaemic hepatitis arising from critical reduction in liver blood flow as occurs with profound shock; drugs which cause intra-hepatic cholestasis or hepatocellular necrosis and total parenteral nutrition which may result in fatty infiltration of the liver. Alcoholic hepatitis, although relatively rare, is occasionally seen in patients presenting to the intensive care unit (ICU). Although patients with this condition are often relatively asymptomatic a small number develop ascites, marked jaundice, encephalopathy and even liver failure. It is important to identify these patients as they may be successfully treated with corticosteroids or pentoxyfylline.
Encephalopathy Norma McAvoy MBChB MRCP is a Specialist Registrar in Gastroenterology at the Royal Infirmary, Edinburgh, UK. Conflicts of interest: none declared.
Hepatic encephalopathy is a reversible neuropsychiatric syndrome, which may complicate acute or chronic liver failure. Graded numerically: (1) mild confusion (GCS 15), (2)lethargy (GCS 12e14), (3) somnolent but rousable (GCS 8e11), (4) comatose (GCS <8), its presence signifies liver failure and should prompt consideration for liver transplantation. Diagnosis is essentially clinical but diagnostic modalities such as electroencephalography (EEG), positron emission tomography (PET) scanning or electrophysiological tests such as visual or brain-stem auditory evoked potentials may be useful if clinical doubt remains.
Euan Thomson BSc MBChB MRCP FRCA is a locum Consultant Anaesthetist at the Royal Infirmary, Edinburgh, UK. Conflicts of interest: none declared. Elizabeth S Wilson BSc MBChB FRCS FRCA FFICM is a Consultant in Critical Care Medicine and Anaesthesia at the Royal Infirmary, Edinburgh, UK. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:4
161
Ó 2012 Elsevier Ltd. All rights reserved.
INTENSIVE CARE
Aetiology
Investigation of liver failure
Common aetiologies of acute and chronic liver failure are indicated in Table 1.
Liver failure
Investigation
Biochemistry
A number of investigations are routinely performed to differentiate between the various causes of liver disease and to monitor disease progression. These are listed in Table 2. Haematology Virology
Pathophysiology of liver failure Disturbance in liver function often results in the dysfunction of multiple other organ systems as indicated in Figure 1.
Immunology Radiology
Management of acute liver failure (ALF) Management is aimed at: preventing further liver injury/promoting hepatocyte recovery supporting failing organ systems avoiding complications.
Endoscopy
Abbreviations: ABG, arterial blood gas; AMA, anti-mitochondrial antibodies; ANA, anti-nuclear antibody; CMV, cytomegalovirus; CT, computed tomography; EBV, Epstein-Barr virus; FBC, full blood count; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; HIV, human immunodeficiency virus; LFTs, liver function tests; SMA, smooth muscle antibodies; LKSA, liver kidney spleen antibodies; PEP, protein electrophoresis; PT, prothrombin time; U&Es, urea and electrolytes.
Aetiology of acute and chronic liver failure Acute liver failure
Chronic liver failure
Drug induced Paracetamol Alcohol Ecstasy Cocaine Halothane Non-steroidal anti-inflammatory drugs Antibiotics: (augmentin, ciprofloxacin, doxycycline, isoniazid, erythromycin) Viral Hepatitis A, B, E Hepatitis B, C, D Cytomegalovirus EpsteineBarr virus Metabolic Wilson’s disease Haemochromatosis Wilsons disease a-1-antitrypsin deficiency Non-alcoholic fatty liver disease Autoimmune hepatitis Autoimmune Autoimmune hepatitisa Primary biliary cirrhosis Primary sclerosing cholangitis BuddeChiari syndrome Vascular BuddeChiari syndrome Portal vein occlusion Hepatic artery thrombosis Ischaemic hepatitis Pregnancy HELLP syndrome Acute fatty liver a
Table 2
Patients should be managed in a critical care environment. Early referral to a liver transplant unit is mandatory for those with acute liver failure and encephalopathy. Cardiovascular system Profound vasodilatation and circulatory collapse often complicate ALF. Management is with judicious volume replacement and vasopressor support (e.g. norepinephrine infusion). Fluid management may be usefully guided by cardiac output monitoring (pulmonary artery catheter/PiCCO etc). Coagulation Coagulation should be assessed at least 12 hourly by laboratory measurement. The prothrombin time, analysed by the Manchester method, is one of the King’s College criteria used to assess suitability for liver transplantation. Routine correction of coagulopathy interferes with the temporal changes occurring in the prothrombin time and consequent transplant assessment. Treatment of coagulopathy should be reserved for those patients with clinical evidence of haemorrhage or prior to high-risk invasive procedures (e.g. insertion of intracranial pressure monitoring devices). Renal function Renal replacement therapy should be instituted in patients with oligo-anuric renal failure. For improved haemodynamic stability, continuous veno-venous haemofiltration (CVVH), utilizing a lactatefree dialysate solution, is the modality of choice in most ICUs.
Acute presentation although patients usually cirrhotic.
Table 1
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:4
U&Es, LFTs, glucose Ca, Mg, PO4 ABGs, including lactate PEP, Immunoglobulins Ferritin, caeruloplasmin FBC, coagulation screen, Manchester PT HAV, HBV, HCV, HDV, HEV CMV, EBV HIV ANA, SMA, LKSA, AMA Chest X-ray Abdominal ultrasound with doppler studies þ/ CT abdomen if any suspicion of chronic liver disease For variceal surveillance (in chronic liver disease)
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Ó 2012 Elsevier Ltd. All rights reserved.
INTENSIVE CARE
Pathophysiology of liver failure Pulmonary dysfunction
Encephalopathy
Renal dysfunction ↓Toxin removal
Hypoglycaemia
Vascular dysfunction
Haemodynamic collapse
Immune dysfunction
↓Synthetic function
Liver Injury
Infection
Varices
Architecture disruption
Ascites
Coagulopathy
Figure 1
Infection Patients should be regularly screened for evidence of infection. Routine antimicrobial chemoprophylaxis is currently only recommended for those patients with grade 3 or 4 encephalopathy, renal failure or awaiting transplantation.
(NAC). NAC may also improve haemodynamic stability and peripheral oxygenation in patients with non-paracetamol-related ALF and should be considered for all patients with ALF. Antiviral therapy should be commenced for those with acute hepatitis B. Liver replacement therapies A variety of devices exist that aim to replace, in part, the function of the injured liver. Devices such as MARS (molecular absorbent and recirculation system), Prometheus (albumin adsorption with haemodialysis) and a variety of bioartificial liver systems are available. These devices, although improving haemodynamic stability and reducing hepatic encephalopathy, do not appear to improve outcome and should be considered as a ‘bridge’ therapy, maintaining stability until a donor transplant organ becomes available or intrinsic liver function recovers.
Glycaemic control Patients with ALF are at risk of developing hypoglycaemia through several mechanisms: diminished glycogen stores, impaired gluconeogenesis and increased circulating insulin. Blood glucose should be measured 2 hourly and corrected as appropriate. Early enteral nutrition should be commenced. Intracranial pressure management ALF is associated with marked cerebral oedema. In those with grade 3 or 4 encephalopathy intracranial pressure (ICP) can escalate rapidly and uncontrollably and is one of the primary causes of death. Consideration should be given to the insertion of an ICP monitoring device (e.g. ICP bolt) .The following measures should be employed to control ICP to less than 20 mmHg: early intubation in grade 3 or 4 encephalopathy modest hyperventilation (PaCO2 4.5e5 kPa) adequate oxygenation (PaO2 >10 kPa) 30 head up position optimize cerebral venous drainage (e.g. avoid tight endotracheal tube ties) adequate sedation detection and treatment of seizures (EEG monitoring for paralysed patients) mannitol/hypertonic saline boluses for acute elevations of ICP barbiturate (thiopentone)induced coma for sustained ICP elevations modest hypothermia (32e34 C).
Management of chronic liver failure All patients with cirrhosis should be under regular review by a specialist. Presentation to critical care may be through development of a recognized complication or subsequent decompensation of the liver disease. Specific management of some common complications are listed. Variceal haemorrhage: oesophageal varices are present in up to 60% of patients at the time of diagnosis of cirrhosis. Thirty percent of patients with cirrhosis and varices will bleed. Mortality associated with the first bleed is up to 50%. Risk factors for variceal bleeding include: portal pressure variceal size severity of liver disease (graded by Child’s Pugh criteria) specific variceal characteristics e.g. red signs. Management of acute variceal haemorrhage e prompt aggressive fluid resuscitation and correction of coagulopathy are warranted. Both clotting factors and 10 mg intravenous vitamin K should be administered as patients are commonly malnourished. Early upper gastrointestinal endoscopy (UGIE) with airway
Specific therapies Paracetamol levels should be measured early in the disease course and suspected toxicity treated with N-acetylcysteine
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:4
163
Ó 2012 Elsevier Ltd. All rights reserved.
INTENSIVE CARE
protection should be performed after adequate fluid resuscitation in a critical care setting. Parenteral antibiotics are administered for 5e10 days as this has been shown to improve outcome. In those patients in whom haemostasis cannot be achieved by endoscopic measures (band ligation or injection of thrombin or cyanoacrylate) a Sengstaken Blakemore tube should be passed and the patient considered for a transjugular intra hepatic portosystemic shunt (TIPSS). The risk of rebleeding following a primary bleed exceeds 60%. Secondary prevention is therefore mandatory and may take several forms: pharmacological: non-selective b-blockers (propranolol/ nadolol) endoscopic surveillance with repeat variceal band ligation transjugular intra hepatic porto-systemic shunt. This has an associated risk of worsening encephalopathy Surgical shunts (rarely used).
King’s College criteria for liver transplantation in acute liver failure1 Paracetamol-related ALF: Either C Arterial pH <7.3 or [H] >50 following resuscitation Or all of the following within 24 hours C Manchester PT >100 seconds C Creatinine > 300 mmol/litre C Grade 3 or 4 encephalopathy Non-paracetamol related ALF: Either C Manchester PT>100 seconds (irrespective of encephalopathy grade) Or three or more of the following variables: C Age <10 or >40 years C Unfavourable cause: non-AeE hepatitis, halothane hepatitis, drug reaction C Duration of jaundice before encephalopathy >7 days C PT >50 seconds C Bilirubin >300 mmol/litre
Spontaneous bacterial peritonitis: approximately 10% of hospital patients with ascites have spontaneous bacterial peritonitis (SBP), defined as the presence of more than 250 neutrophils per ml. Patients are often asymptomatic. Consequently, those patients with ascites should have a diagnostic tap for exclusion purposes. Treatment is with appropriate parenteral antibiotics, such as third generation cephalosporins. Intravenous albumin has been shown to reduce the incidence of complications such as hepatorenal syndrome and improve survival. The recurrence rate of SBP is high and secondary prophylaxis with cotrimoxazole is indicated in all patients. The long-term prognosis for patients with SBP is poor, with mortality rates in excess of 70% reported at 2 years. Therefore patients who have recovered from one episode should be considered for liver transplantation.
ALF, acute liver failure; PT, prothrombin time.
Table 3
advent of liver transplantation survival rates now exceed 80%. For most patients transplantation is the only definitive treatment available. Donor livers are however a scarce resource and suitability of the recipient for transplantation must be carefully considered. A number of systems exist for identifying patients appropriate for transplantation, of which the King’s College criteria (Table 3) is the most commonly used.
Encephalopathy: management of hepatic encephalopathy in patients with chronic liver disease is predominantly supportive (e.g. adequate hydration and withdrawal of precipitating factors). Pharmacological measures include lactulose, to reduce gut transit time and ammonia absorption, and L-ornithine-L-aspartate (LOLA), which promotes the conversion of ammonia to non-toxic urea. These have been shown to significantly decrease ammonia levels, improve mental state parameters and EEG activity. Poorly absorbed antibiotics such as neomycin and rifaximin which reduce gut flora and ammonia production are also used.
Chronic liver failure: for many years the prognosis of a patient with cirrhosis has been assessed using the Child-Pugh score (Table 4). Individual components are added together to give the Child-Pugh score (grade A: <7, grade B: 7e9, grade C: >9). Survival in grade C is less than 12 months without transplantation. The MELD score (Model for End-stage Liver Disease) can also be used to predict mortality, in patients with end-stage liver failure and increasingly is being utilized to rank patients in order of priority for elective liver transplantation.
Hepatorenal syndrome: end-stage liver disease, both chronic and acute, can lead to the development of hepatorenal syndrome in which intense reno-vasocontriction and splanchnic vasodilation lead to progressive renal failure without intrinsic renal injury. The development of this complication is an ominous sign and is associated with a high mortality. Current treatment is based on improving circulatory integrity by reversing splanchnic vasodilation with agents such as terlipressin and expanding circulating volume with intravenous albumin supplementation.
Child Pugh score
Encephalopathy Bilirubin (Bilirubin in PBC or PSC) Albumin PT (seconds prolonged) Ascites
Prognosis and transplantation Acute liver failure: previously, the mortality associated with severe acute liver failure exceeded 80%. However, with the
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:4
1
2
3
None <34 <68 >35 <4 None
Mild 34e50 68e170 28e35 4e6 Mild
Marked >50 >170 <28 >6 Marked
Table 4
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Ó 2012 Elsevier Ltd. All rights reserved.
INTENSIVE CARE
be maintained to ensure early appropriate therapy is delivered. For many, their only realistic hope of prolonged survival is liver transplantation and early referral to a liver transplant unit is mandatory. A
MELD ¼ 9:6 loge ðcreatinine mg=dlÞ þ 3:8 loge ðbilirubin mg=dlÞ þ 11:2 loge ðINRÞ þ 6:4 In hospitalized patients the MELD score predicts 3 month mortality as: >40 ¼ 71.3%, 30e39 ¼ 52.6%, 20e29 ¼ 19.6%, 10e19 ¼ 6%, <9 ¼ 1.9%.
Summary
REFERENCE 1 Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterol 1989; 97: 439e45.
The management of patients with liver failure presents a very significant challenge to the critical care physician. Since the normal functioning liver is central to many homeostatic mechanisms, liver failure should be considered as a multi-system illness rather than a single organ dysfunction. Patients with liver failure have complex and often rapidly changing physiological abnormalities and, although best managed in a critical care environment, their optimal treatment relies on careful collaboration between critical care, hepatology and transplant teams. Frequently the patient with liver failure presents with a variety of non-specific symptoms and so a high index of suspicion should
FURTHER READING Claridge LC. Rising liver death rate: food for thought. Lancet 2011; 377: 2179e80. Craig D, Lee A, Hayes P, Simpson K. Review article: the current management of acute liver failure. Aliment Pharmacol Ther 2010; 31: 345e58. Larsen F, Bjerring P. Acute liver failure. Curr Opin Crit Care 2011; 17: 160e4. Goldberg E, Chopra S. UpToDate. Overview of the complications, prognosis and management of cirrhosis. Sauk J, Friedman SL. UpToDate. Prognosis and treatment of alcoholic liver disease and alcoholic hepatitis.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:4
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Ó 2012 Elsevier Ltd. All rights reserved.
Hepatic failure
Learning objectives
Norma McAvoy After reading this article you should be able to: C recognise the differences in presentation of acute and chronic liver failure C investigate and manage patients with liver disease in the intensive care unit C understand why liver disease results in the dysfunction of multiple organ systems
Euan Thomson Elizabeth S Wilson
Abstract The incidence of liver disease is increasing in the UK, attributable to a surge in excessive alcohol consumption and obesity. It is therefore not surprising that intensive care units are managing more patients with chronic liver disease. These individuals are often malnourished and can rapidly progress to multi-organ failure, requiring prolonged spells of organ support. However the spectrum of liver dysfunction encountered in the critical care setting is quite diverse and includes patients with: acute liver failure decompensation of chronic liver disease and associated complications impaired liver function secondary to severe systemic illness and its treatment. In this article we describe the aetiology, investigation, management and prognosis of patients presenting to critical care with severe liver impairment. Transplantation has radically modified the outcome for many patients and early specialist referral should be considered.
Chronic liver failure In contrast, chronic liver disease arises when the normal cytoarchitecture of the liver is gradually destroyed. Normal hepatic tissue is progressively replaced by scar tissue (cirrhosis). This results not only in gradual diminution of normal metabolic and synthetic hepatic function but also alteration in liver blood flow and development of portal hypertension. Liver failure is said to be present when either ascites or encephalopathy is present. The signs and symptoms of chronic liver disease reflect a slow progressive deterioration in liver function. They include fatigue, itch, weight loss, progressive jaundice, ascites, encephalopathy and stigmata of chronic liver disease (e.g. spider naevi). However, even patients with advanced chronic liver disease may be relatively asymptomatic. These patients often come to the attention of critical care following an acute worsening of symptoms precipitated by an additional insult, for example variceal haemorrhage, systemic infection or spontaneous bacterial peritonitis.
Keywords Encephalopathy; liver failure; management; pathophysiology; prognosis; transplant criteria
Acute liver failure
Liver dysfunction in critical illness
Liver failure can develop rapidly in patients with previously normal hepatic function. The predominant mechanism of action is destruction of hepatocytes. Previously the term ‘fulminant hepatic failure’ was attributed to hepatic failure with encephalopathy presenting within 8 weeks of first symptoms of liver injury, in patients without pre-existing liver disease. More recently the terms hyperacute, acute and subacute liver failure have gained widespread use, reflecting time from development of jaundice to encephalopathy of 0e7 days, 8e28 days and 4e12 weeks respectively. Symptoms of acute liver failure are often initially mild and non-specific (e.g. abdominal pain and nausea), but rapidly progress to include jaundice, coagulopathy and encephalopathy.
Critically ill patients can develop liver dysfunction in the absence of primary hepatic disease. Common causes include ischaemic hepatitis arising from critical reduction in liver blood flow as occurs with profound shock; drugs which cause intra-hepatic cholestasis or hepatocellular necrosis and total parenteral nutrition which may result in fatty infiltration of the liver. Alcoholic hepatitis, although relatively rare, is occasionally seen in patients presenting to the intensive care unit (ICU). Although patients with this condition are often relatively asymptomatic a small number develop ascites, marked jaundice, encephalopathy and even liver failure. It is important to identify these patients as they may be successfully treated with corticosteroids or pentoxyfylline.
Encephalopathy Norma McAvoy MBChB MRCP is a Specialist Registrar in Gastroenterology at the Royal Infirmary, Edinburgh, UK. Conflicts of interest: none declared.
Hepatic encephalopathy is a reversible neuropsychiatric syndrome, which may complicate acute or chronic liver failure. Graded numerically: (1) mild confusion (GCS 15), (2)lethargy (GCS 12e14), (3) somnolent but rousable (GCS 8e11), (4) comatose (GCS <8), its presence signifies liver failure and should prompt consideration for liver transplantation. Diagnosis is essentially clinical but diagnostic modalities such as electroencephalography (EEG), positron emission tomography (PET) scanning or electrophysiological tests such as visual or brain-stem auditory evoked potentials may be useful if clinical doubt remains.
Euan Thomson BSc MBChB MRCP FRCA is a locum Consultant Anaesthetist at the Royal Infirmary, Edinburgh, UK. Conflicts of interest: none declared. Elizabeth S Wilson BSc MBChB FRCS FRCA FFICM is a Consultant in Critical Care Medicine and Anaesthesia at the Royal Infirmary, Edinburgh, UK. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:4
161
Ó 2012 Elsevier Ltd. All rights reserved.
INTENSIVE CARE
Aetiology
Investigation of liver failure
Common aetiologies of acute and chronic liver failure are indicated in Table 1.
Liver failure
Investigation
Biochemistry
A number of investigations are routinely performed to differentiate between the various causes of liver disease and to monitor disease progression. These are listed in Table 2. Haematology Virology
Pathophysiology of liver failure Disturbance in liver function often results in the dysfunction of multiple other organ systems as indicated in Figure 1.
Immunology Radiology
Management of acute liver failure (ALF) Management is aimed at: preventing further liver injury/promoting hepatocyte recovery supporting failing organ systems avoiding complications.
Endoscopy
Abbreviations: ABG, arterial blood gas; AMA, anti-mitochondrial antibodies; ANA, anti-nuclear antibody; CMV, cytomegalovirus; CT, computed tomography; EBV, Epstein-Barr virus; FBC, full blood count; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; HIV, human immunodeficiency virus; LFTs, liver function tests; SMA, smooth muscle antibodies; LKSA, liver kidney spleen antibodies; PEP, protein electrophoresis; PT, prothrombin time; U&Es, urea and electrolytes.
Aetiology of acute and chronic liver failure Acute liver failure
Chronic liver failure
Drug induced Paracetamol Alcohol Ecstasy Cocaine Halothane Non-steroidal anti-inflammatory drugs Antibiotics: (augmentin, ciprofloxacin, doxycycline, isoniazid, erythromycin) Viral Hepatitis A, B, E Hepatitis B, C, D Cytomegalovirus EpsteineBarr virus Metabolic Wilson’s disease Haemochromatosis Wilsons disease a-1-antitrypsin deficiency Non-alcoholic fatty liver disease Autoimmune hepatitis Autoimmune Autoimmune hepatitisa Primary biliary cirrhosis Primary sclerosing cholangitis BuddeChiari syndrome Vascular BuddeChiari syndrome Portal vein occlusion Hepatic artery thrombosis Ischaemic hepatitis Pregnancy HELLP syndrome Acute fatty liver a
Table 2
Patients should be managed in a critical care environment. Early referral to a liver transplant unit is mandatory for those with acute liver failure and encephalopathy. Cardiovascular system Profound vasodilatation and circulatory collapse often complicate ALF. Management is with judicious volume replacement and vasopressor support (e.g. norepinephrine infusion). Fluid management may be usefully guided by cardiac output monitoring (pulmonary artery catheter/PiCCO etc). Coagulation Coagulation should be assessed at least 12 hourly by laboratory measurement. The prothrombin time, analysed by the Manchester method, is one of the King’s College criteria used to assess suitability for liver transplantation. Routine correction of coagulopathy interferes with the temporal changes occurring in the prothrombin time and consequent transplant assessment. Treatment of coagulopathy should be reserved for those patients with clinical evidence of haemorrhage or prior to high-risk invasive procedures (e.g. insertion of intracranial pressure monitoring devices). Renal function Renal replacement therapy should be instituted in patients with oligo-anuric renal failure. For improved haemodynamic stability, continuous veno-venous haemofiltration (CVVH), utilizing a lactatefree dialysate solution, is the modality of choice in most ICUs.
Acute presentation although patients usually cirrhotic.
Table 1
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:4
U&Es, LFTs, glucose Ca, Mg, PO4 ABGs, including lactate PEP, Immunoglobulins Ferritin, caeruloplasmin FBC, coagulation screen, Manchester PT HAV, HBV, HCV, HDV, HEV CMV, EBV HIV ANA, SMA, LKSA, AMA Chest X-ray Abdominal ultrasound with doppler studies þ/ CT abdomen if any suspicion of chronic liver disease For variceal surveillance (in chronic liver disease)
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Ó 2012 Elsevier Ltd. All rights reserved.
INTENSIVE CARE
Pathophysiology of liver failure Pulmonary dysfunction
Encephalopathy
Renal dysfunction ↓Toxin removal
Hypoglycaemia
Vascular dysfunction
Haemodynamic collapse
Immune dysfunction
↓Synthetic function
Liver Injury
Infection
Varices
Architecture disruption
Ascites
Coagulopathy
Figure 1
Infection Patients should be regularly screened for evidence of infection. Routine antimicrobial chemoprophylaxis is currently only recommended for those patients with grade 3 or 4 encephalopathy, renal failure or awaiting transplantation.
(NAC). NAC may also improve haemodynamic stability and peripheral oxygenation in patients with non-paracetamol-related ALF and should be considered for all patients with ALF. Antiviral therapy should be commenced for those with acute hepatitis B. Liver replacement therapies A variety of devices exist that aim to replace, in part, the function of the injured liver. Devices such as MARS (molecular absorbent and recirculation system), Prometheus (albumin adsorption with haemodialysis) and a variety of bioartificial liver systems are available. These devices, although improving haemodynamic stability and reducing hepatic encephalopathy, do not appear to improve outcome and should be considered as a ‘bridge’ therapy, maintaining stability until a donor transplant organ becomes available or intrinsic liver function recovers.
Glycaemic control Patients with ALF are at risk of developing hypoglycaemia through several mechanisms: diminished glycogen stores, impaired gluconeogenesis and increased circulating insulin. Blood glucose should be measured 2 hourly and corrected as appropriate. Early enteral nutrition should be commenced. Intracranial pressure management ALF is associated with marked cerebral oedema. In those with grade 3 or 4 encephalopathy intracranial pressure (ICP) can escalate rapidly and uncontrollably and is one of the primary causes of death. Consideration should be given to the insertion of an ICP monitoring device (e.g. ICP bolt) .The following measures should be employed to control ICP to less than 20 mmHg: early intubation in grade 3 or 4 encephalopathy modest hyperventilation (PaCO2 4.5e5 kPa) adequate oxygenation (PaO2 >10 kPa) 30 head up position optimize cerebral venous drainage (e.g. avoid tight endotracheal tube ties) adequate sedation detection and treatment of seizures (EEG monitoring for paralysed patients) mannitol/hypertonic saline boluses for acute elevations of ICP barbiturate (thiopentone)induced coma for sustained ICP elevations modest hypothermia (32e34 C).
Management of chronic liver failure All patients with cirrhosis should be under regular review by a specialist. Presentation to critical care may be through development of a recognized complication or subsequent decompensation of the liver disease. Specific management of some common complications are listed. Variceal haemorrhage: oesophageal varices are present in up to 60% of patients at the time of diagnosis of cirrhosis. Thirty percent of patients with cirrhosis and varices will bleed. Mortality associated with the first bleed is up to 50%. Risk factors for variceal bleeding include: portal pressure variceal size severity of liver disease (graded by Child’s Pugh criteria) specific variceal characteristics e.g. red signs. Management of acute variceal haemorrhage e prompt aggressive fluid resuscitation and correction of coagulopathy are warranted. Both clotting factors and 10 mg intravenous vitamin K should be administered as patients are commonly malnourished. Early upper gastrointestinal endoscopy (UGIE) with airway
Specific therapies Paracetamol levels should be measured early in the disease course and suspected toxicity treated with N-acetylcysteine
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:4
163
Ó 2012 Elsevier Ltd. All rights reserved.
INTENSIVE CARE
protection should be performed after adequate fluid resuscitation in a critical care setting. Parenteral antibiotics are administered for 5e10 days as this has been shown to improve outcome. In those patients in whom haemostasis cannot be achieved by endoscopic measures (band ligation or injection of thrombin or cyanoacrylate) a Sengstaken Blakemore tube should be passed and the patient considered for a transjugular intra hepatic portosystemic shunt (TIPSS). The risk of rebleeding following a primary bleed exceeds 60%. Secondary prevention is therefore mandatory and may take several forms: pharmacological: non-selective b-blockers (propranolol/ nadolol) endoscopic surveillance with repeat variceal band ligation transjugular intra hepatic porto-systemic shunt. This has an associated risk of worsening encephalopathy Surgical shunts (rarely used).
King’s College criteria for liver transplantation in acute liver failure1 Paracetamol-related ALF: Either C Arterial pH <7.3 or [H] >50 following resuscitation Or all of the following within 24 hours C Manchester PT >100 seconds C Creatinine > 300 mmol/litre C Grade 3 or 4 encephalopathy Non-paracetamol related ALF: Either C Manchester PT>100 seconds (irrespective of encephalopathy grade) Or three or more of the following variables: C Age <10 or >40 years C Unfavourable cause: non-AeE hepatitis, halothane hepatitis, drug reaction C Duration of jaundice before encephalopathy >7 days C PT >50 seconds C Bilirubin >300 mmol/litre
Spontaneous bacterial peritonitis: approximately 10% of hospital patients with ascites have spontaneous bacterial peritonitis (SBP), defined as the presence of more than 250 neutrophils per ml. Patients are often asymptomatic. Consequently, those patients with ascites should have a diagnostic tap for exclusion purposes. Treatment is with appropriate parenteral antibiotics, such as third generation cephalosporins. Intravenous albumin has been shown to reduce the incidence of complications such as hepatorenal syndrome and improve survival. The recurrence rate of SBP is high and secondary prophylaxis with cotrimoxazole is indicated in all patients. The long-term prognosis for patients with SBP is poor, with mortality rates in excess of 70% reported at 2 years. Therefore patients who have recovered from one episode should be considered for liver transplantation.
ALF, acute liver failure; PT, prothrombin time.
Table 3
advent of liver transplantation survival rates now exceed 80%. For most patients transplantation is the only definitive treatment available. Donor livers are however a scarce resource and suitability of the recipient for transplantation must be carefully considered. A number of systems exist for identifying patients appropriate for transplantation, of which the King’s College criteria (Table 3) is the most commonly used.
Encephalopathy: management of hepatic encephalopathy in patients with chronic liver disease is predominantly supportive (e.g. adequate hydration and withdrawal of precipitating factors). Pharmacological measures include lactulose, to reduce gut transit time and ammonia absorption, and L-ornithine-L-aspartate (LOLA), which promotes the conversion of ammonia to non-toxic urea. These have been shown to significantly decrease ammonia levels, improve mental state parameters and EEG activity. Poorly absorbed antibiotics such as neomycin and rifaximin which reduce gut flora and ammonia production are also used.
Chronic liver failure: for many years the prognosis of a patient with cirrhosis has been assessed using the Child-Pugh score (Table 4). Individual components are added together to give the Child-Pugh score (grade A: <7, grade B: 7e9, grade C: >9). Survival in grade C is less than 12 months without transplantation. The MELD score (Model for End-stage Liver Disease) can also be used to predict mortality, in patients with end-stage liver failure and increasingly is being utilized to rank patients in order of priority for elective liver transplantation.
Hepatorenal syndrome: end-stage liver disease, both chronic and acute, can lead to the development of hepatorenal syndrome in which intense reno-vasocontriction and splanchnic vasodilation lead to progressive renal failure without intrinsic renal injury. The development of this complication is an ominous sign and is associated with a high mortality. Current treatment is based on improving circulatory integrity by reversing splanchnic vasodilation with agents such as terlipressin and expanding circulating volume with intravenous albumin supplementation.
Child Pugh score
Encephalopathy Bilirubin (Bilirubin in PBC or PSC) Albumin PT (seconds prolonged) Ascites
Prognosis and transplantation Acute liver failure: previously, the mortality associated with severe acute liver failure exceeded 80%. However, with the
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:4
1
2
3
None <34 <68 >35 <4 None
Mild 34e50 68e170 28e35 4e6 Mild
Marked >50 >170 <28 >6 Marked
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be maintained to ensure early appropriate therapy is delivered. For many, their only realistic hope of prolonged survival is liver transplantation and early referral to a liver transplant unit is mandatory. A
MELD ¼ 9:6 loge ðcreatinine mg=dlÞ þ 3:8 loge ðbilirubin mg=dlÞ þ 11:2 loge ðINRÞ þ 6:4 In hospitalized patients the MELD score predicts 3 month mortality as: >40 ¼ 71.3%, 30e39 ¼ 52.6%, 20e29 ¼ 19.6%, 10e19 ¼ 6%, <9 ¼ 1.9%.
Summary
REFERENCE 1 Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterol 1989; 97: 439e45.
The management of patients with liver failure presents a very significant challenge to the critical care physician. Since the normal functioning liver is central to many homeostatic mechanisms, liver failure should be considered as a multi-system illness rather than a single organ dysfunction. Patients with liver failure have complex and often rapidly changing physiological abnormalities and, although best managed in a critical care environment, their optimal treatment relies on careful collaboration between critical care, hepatology and transplant teams. Frequently the patient with liver failure presents with a variety of non-specific symptoms and so a high index of suspicion should
FURTHER READING Claridge LC. Rising liver death rate: food for thought. Lancet 2011; 377: 2179e80. Craig D, Lee A, Hayes P, Simpson K. Review article: the current management of acute liver failure. Aliment Pharmacol Ther 2010; 31: 345e58. Larsen F, Bjerring P. Acute liver failure. Curr Opin Crit Care 2011; 17: 160e4. Goldberg E, Chopra S. UpToDate. Overview of the complications, prognosis and management of cirrhosis. Sauk J, Friedman SL. UpToDate. Prognosis and treatment of alcoholic liver disease and alcoholic hepatitis.
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