Clinical Anesthesia Arun Kumar Paul
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Anaesthesia and Liver DiseasesCHAPTER 1

Anaesthesia and surgery may adversely affect liver functions even in normal subjects and more so in the presence of liver diseases. Liver dysfunction has important implications for the anaesthetic management in such cases. Anaesthetist should have a clear understanding of the physiologic functions of the liver and various tests related to them and the pathophysiology of hepatic diseases to assess the type and extent of organ dysfunction from the point of view of determining proper anaesthesia care.
Important functions of the liver include glucose homeostasis, protein synthesis, drug binding, drug metabolism, formation of clotting factors, hydrolysis of ester linkages, bilirubin formation, excretion and reticuloendothelial activity.
Carbohydrate Metabolism
Liver is the main organ for storage and release of glucose. Glucose is stored as glycogen in liver. Glycogenolysis helps to maintain normal blood glucose level. Liver can store about 75 gm glycogen and this can be depleted within 48 hours of starvation. In depletion of glycogen stores maintenance of glucose level mainly depends on gluconeogenesis, that is, a conversion of lactate, glycerol and amino acids to glucose. Cirrhotic patients are at risk of hypoglycaemia in perioperative period.
Protein Synthesis
All proteins except gammaglobulin and factor VIII are synthesised in the endoplasmic reticulum of hepatocytes. Decreased levels of these substances lead to drug binding and haemostatic problems. Plasma level of serum 2albumin between 3.5 to 5.5 gm % is maintained by the production of about 10 to 15 gm daily in the liver. Low serum level (less than 2.5 gm%) produces an increase in unbound drug activity and a much intense drug response. The half-life of albumin is about 20 days and thus acute hepatic dysfunction may not be reflected by decreased plasma albumin level.
Most procoagulants are synthesised by the hepatocytes and in liver dysfunction, there is inadequacy of these clotting factors. The estimation of prothrombin time, partial thromboplastin time and bleeding time are always useful. It should be noted that only 20 to 30% of the normal level of clotting factors are needed to prevent bleeding. Thus, liver function must be much depressed before clinical manifestations of impaired coagulation. However, the plasma half-life of prothrombin and fibrinogen is short and thus acute liver dysfunction may be associated with clotting problems. In cases of liver dysfunction, bleeding problem may also be due to inability of the liver to clear plasma activators of the fibrinolytic system. In presence of liver dysfunction along with splenomegaly, platelets are trapped in the spleen and thus coagulation may suffer.
Drug Metabolism
Most of the drugs are metabolised in liver with the help of microsomal enzymes present in smooth endoplasmic reticulum of hepatocytes. Chronic dysfunction of liver causes derangement of drug metabolism due to either decreased enzyme containing hepatocytes or decreased liver blood flow or both. Thus, the drug effect may be prolonged.
Accelerated drug metabolism may also occur due to stimulation of enzyme activity, the so called enzyme induction particularly in cases of cirrhosis of liver.
Hydrolysis of Ester Linkages
The level of serum pseudocholinesterase is decreased significantly in presence of severe liver disease. This hampers the hydrolysis of ester linkages in certain drugs like suxamethonium, mivacurium, propanidid and ester local anaesthetics. The plasma half-life of plasma cholinesterase is about 14 days, so acute liver failure may not manifest the prolonged effect following suxamethonium.3
Bilirubin Metabolism
Bilirubin is formed in the reticuloendothelial system from the breakdown of haemoglobin. This bilirubin becomes bound with albumin and transported and conjugated in the liver and excreted in the bile. Protein bound unconjugated bilirubin is not water soluble and thus, its excretion through urine is minimum. Conjugated bilirubin (with glucoronic acid) in the liver is water soluble and its small amount enters the circulation and is excreted in urine. The other part is excreted into the small intestine through bile canaliculi. Defects in the ability to metabolise breakdown products of haemoglobin will cause hyperbilirubinaemia and eventually jaundice and toxic effects.
In jaundice, bilirubin is found in body fluids like CSF, joint fluid, cysts, but absent in true secretions like tears, saliva and pancreative juice.
Reticuloendothelial Activity
Liver is the major organ of reticuloendothelial activity (about 85%). It helps in elimination of gastrointestinal toxins and bacterial endotoxins. It also helps to eliminate ammonia. In severe liver dysfunction accumulation of ammonia may initiate hepatic encephalopathy.
Lactic acid is formed peripherally but metabolised in liver. Liver dysfunction may cause metabolic acidosis due to inability to metabolise lactic acid.
Liver function tests are important to detect the presence of liver disease preoperatively. It also helps for the differential diagnosis of postoperative liver dysfunction.
  1. Serum bilirubin: 0.3 to 1.2 mg/100 ml; upto 17 µ mol/litre (sum total of conjugated and unconjugated bilirubin). Conjugated bilirubin 0.1 to 0.4 mg/100 ml, unconjugated bilirubin 0.2 to 0.8 mg/100 ml. Jaundice is latent (clinically non-evident) when serum bilirubin is in between 1 and 2.5 mg/100 ml.
  2. Van den Bergh test:
    1. Direct positive in conjugated hyperbilirubinaemia as in obstructive jaundice.
    2. Indirect positive in unconjugated hyperbilirubinaemia as in haemolytic jaundice.
    3. Biphasic as in hepatocellular jaundice.
  3. Serum alkaline phosphatase: Normal 3 to 13 KA units/100 ml; haemolytic jaundice 3 to 13 KA units; hepatocellular jaundice 15 to 30 KA units; obstructive jaundice more than 30 KA units/100 ml.
  4. Serum protein: Normal values – albumin 4 to 5.5 g/100 ml, globulin 1.5 to 3 g/100 ml, fibrinogen 0.2 to 0.5 g/100 ml, Total 6 to 8 g/100 ml.
    In haemolytic jaundice – normal; In hepatocellular jaundice – increased γ globulin, diminished serum albumin α2 and β globulin; in obstructive jaundice – increased α2 globulin.
    Albumin is synthesised in the liver and has a half-life of about 20 days. Thus, its level may indicate degree of liver dysfunction, more in chronic liver disease than in acute hepatic failure.
  5. Serum transaminases:
    SGOT (aspertate aminotransferase) 5 to 17 IU/lit.
    SGPT (alanine aminotransferase) 4 to 13 IU/lit.
    In haemolytic jaundice—normal; hepatocellular jaundice – great increase in acute necrosis, moderate increase in cirrhosis; obstructive jaundice – mild increase.
    SGPT is more specific for liver disease than SGOT as it is also present in heart and skeletal muscles.
  6. Stool examination: Haemolytic jaundice – dark coloured; hepatocellular jaundice – usually normal; obstructive jaundice – pale.
  7. Urine examination:
    Haemolytic jaundice: no bilirubin, urobilinogen ++
    Hepatocellular jaundice: variable bilirubin, urobilinogen ++
    Obstructive jaundice: bilirubin ++, no urobilinogen.
  8. Lactate dehydrogenase: Normal upto 500 IU/lit. It is elevated in infective or toxic hepatitis, but is usually normal in early obstructive jaundice. It is a relatively insensitive indicator of liver damage as the enzyme is widely distributed in other tissues.
  9. Prothrombin time: Normal 12 to 14 seconds. It is elevated in jaundiced patient and must always be monitored. Correction with vitamin K suggests extrahepatic obstruction.
    Prothrombin (factor II) is produced solely in liver and its level or determination of prothrombin time provide a good index of liver function.
  10. Pseudocholinesterase level: Normal 40 to 100 units/100 ml. Low pseudocholinesterase level is common in liver diseases.
  11. Bromsulphthalein test: This dye is taken up by the liver cells and excreted unchanged in bile. Five per cent bromsulphthalein 5 mg/kg is given IV and if normal, 0 to 3% of it should be in the blood after 45 minutes.
  12. Radiology:
    Oral cholecystogram
    Intravenous cholangiogram
    Percutaneous cholangiography
    Endoscopy examination of biliary tract with retrograde cholangiography.
  13. Radioactive scans
  14. Liver biopsy: It should not be done, if prothrombin time is 3 seconds increased over the control or if the platelet count is below 80000/mm3. Caution should also be taken in presence of severe deep jaundice or if there is any possibility of cholangitis because of risks of biliary leak and septicaemia.
      Diseases of liver impair the normal metabolic, detoxicating and excretory functions and produce widespread effects on circulation and general state of the patient. As the liver has large reserves and enormous capacity for repair, there may be gross pathological changes with relatively little alteration in individual tests. Thus, liver functions are rarely specific.
  1. Most of the anaesthetic drugs are metabolised in the liver with the help of microsomal enzymes.
  2. Barbiturates: Most barbiturates undergo metabolic transformation in liver. Metabolism of thiopentone by oxidation to the corresponding carboxylic acid occurs in liver, 10 to 15% of the drug in the body is metabolised each hour. Muscular tissue and kidneys may also help in its detoxication. However, the degree and duration of effect of barbiturates given IV are dependent on redistribution and tissue uptake. N-methyl substituted oxybarbiturates may be inactivated by demethylation, but methylated oxybarbiturate, methohexitone undergoes hydroxylation.
  3. Other IV anaesthetics: Propanidid is broken down by esterases in the liver and plasma. Metabolic pathways involved in metabolism are splitting of ester linkage and diethyl aminogroup, 90% of propanidid is excreted as inactive metabolites in urine. Althesin undergoes active hepatic metabolism and the breakdown products are excreted in bile, 70% appears 6in faeces and about 30% in urine following enterohepatic circulation. Midazolam undergoes hepatic metabolism and the metabolites are mostly inactive. Etomidate is broken down by hydrolysis in liver and plasma, 87% is excreted in urine and about 13% is excreted in bile. Ketamine undergoes extensive hepatic metabolism and the breakdown products are excreted in urine. Propofol is metabolised in liver to inactive metabolites.
  4. Inhalational anaesthetics: Most volatile anaesthetics undergo biotransformation in liver. Metabolism of ethers and halogenated hydrocarbon drugs occur by dehalogenation. Halothane 20%, enflurane 2% and isoflurane 0.2% metabolise by hepatic microsomal system. The incidence of liver dysfunction following enflurane exposure is much lower than that after halothane. Isoflurane presents least liver damage due to its much less metabolism.
    Trichlorethylene: Twenty percent metabolise to trichloroethanol and trichloracetic acid. Metabolic products are found in urine upto 18 days following anaesthesia.
    Cyclopropane and ethylene are metabolised to some extent. Nitrous oxide is least metabolised amongst all inhalational anaesthetics.
  5. Local anaesthetics: The amide group of drugs like mepivacaine, bupivacaine, etidocaine, prilocaine, lignocaine and cinchocaine are metabolised by microsomal enzymes of liver. The ester drugs like procaine, chloroprocaine and tetracaine are mostly hydrolysed in liver and by plasma cholinesterase.
  6. Relaxant drugs: Tubocurarine is 75% excreted in urine in 24 hours and 11.3% excreted in urine. Gallamine and alcuronium undergo no metabolism, excreted entirely in urine. Pancuronium is eliminated by renal (approx. 30%) and biliary (approx. 24%) routes in unaltered form, some 30% being eliminated as hydroxylated derivative. Metocurine is eliminated mostly by renal route. Vecuronium is excreted by both kidneys (20%) and bile (12%). Pipecuronium undergoes nearly 10% hepatic degradation and its renal excretion is 70% unchanged and biliary excretion is 20% unchanged. Hepatic degradation is mostly insignificant in doxacurium and 70% of it is excreted unchanged and 30% in urine unchanged. Rocuronium undergoes hepatic degradation (10 to 20%). Its urinary excretion is only 10 to 25% (unchanged) and biliary excretion is 50 to 70% (unchanged). Atracurium has no hepatic degradation. It is 7spontaneously degraded by Hofmann reaction and also by enzymatic hydrolysis in plasma. Its biliary and renal excretion is insignificant. Mivacurium undergoes negligible hepatic degradation and mostly hydrolysed in plasma. Its renal and biliary excretion is insignificant.
  7. Most narcotic drugs like morphine, pethidine, etc. are metabolised in liver and excreted in the urine in inactive forms. Nalorphine is inactivated entirely in liver. Phenothiazine derivatives are detoxicated by hepatic enzymes.
  8. Catecholamines, most vasopressor drugs, atropine and hyoscine are extensively metabolised in liver.
  1. Haemolysis: Methyl dopa, phenacetin.
    Clinical features: Drug-induced haemolytic anaemia, no abnormality in hepatic enzyme studies, raised unconjugated bilirubin, direct Coombs’ test positive, increased reticulocyte count.
  2. Hepatotoxicity:
    1. CPredictable, dose related: Carbon tetrachloride, paracetamol, tetracycline high doses IV, chloroform.
    2. Hypersensitivity: MAO inhibitors, methyl dopa, halothane, isoniazid.
    Clinical features: Transaminases level elevated, moderate increase of alkaline phosphatase, fever, eosinophilia.
  3. Cholestatic: Anabolic and androgenic steroids, oral contraceptives.
    Clinical features: Elevation of serum alkaline phosphatase, rise of conjugated bilirubin, slight or no alteration of serum transaminases.
  4. Mixed: Hepatitis like and cholestasis: Phenothiazines, chlordiazepoxide, tricyclic antidepressants, phenylbutazone, sulphonamide, erythromycin, chlorpropamide.
    Clinical features: Hypersensitivity reaction to drugs in susceptible patients, hepatocellular involvement, elevated alkaline phosphatase level.
  1. Following general anaesthesia with various agents, there may be transient mild impairment of liver cell activity as shown by liver function tests. General anaesthesia and regional analgesia may decrease hepatic blood flow by 20 to 30% even in absence of surgical stimulation. There may be 8significant changes on the perfusion pressure or splanchnic vascular resistance or both due to effects of drugs and techniques of anaesthesia.
    Hepatic blood flow is determined by perfusion pressure (mean arterial pressure or portal venous pressure minus hepatic venous pressure) and splanchnic vascular resistance.
    Splanchnic vessels are innervated by vasoconstrictor nerve fibres from sympathetic nervous system. Hypoxia, hypercarbia and increased catecholamines increase splanchnic vascular resistance and reduce liver blood flow. Hepatic blood flow is also influenced by beta receptors. Beta blockers may decrease the hepatic blood flow. IPPV and congestive cardiac failure may also lower hepatic blood flow by increasing central venous pressure and thus hepatic venous pressure and thereby decreasing hepatic perfusion pressure.
    Surgical stimulation and nearness to the operative site to liver may significantly reduce the hepatic blood flow particularly during general anaesthesia.
  2. Inhalational anaesthetics:
    1. Chloroform: It causes severe liver cell damage, centrilobular necrosis being the histological picture. It is dose-related direct hepatotoxic drug. Toxicity is exaggerated in poor nutritional state, poor glycogen reserve, uncontrolled dose of chloroform, hypoxia, hypercarbia, sepsis and hypotension. Damage caused by chloroform is a result of products of its metabolism.
    2. Diethyl ether: It is one of the safest anaesthetic agents with lowest rates of hepatic damage and mortality. Ether stimulates gluconeogenesis (glycogen → glucose) and may cause hyperglycaemia. In depleted glycogen stores, ketone bodies may be formed and thereby produce metabolic acidosis. 85 to 90% of ether is exhaled unchanged via lungs. Only about 4% is metabolised in liver to acetaldehyde and ethanol.
    3. Methoxyflurane: It is reported to cause severe hepatic dysfunction. Its clinical picture resembles that of viral hepatitis. The mechanism of damage is not clearly understood. It is said that an immune mediated response is involved and cross sensitivity with halothane may contribute. Renal damage is dose related and due to fluoride ion production but hepatic damage is not of that type.
    4. Halothane: Halothane itself is not hepatotoxic, but there are a small number of cases who develop jaundice following halothane anaesthesia. Halothane has a reductive metabolic pathway with intermediate hepatotoxic metabolites. These metabolites are capable of bonding covalently to hepatocyte macromolecules leading to hepatocellular damage. Another view is that halothane or any of its metabolites react with hepatocyte proteins to form antigenic compounds, against which the body reacts with an immune response and hepatocellular damage results.
      The risk of postoperative liver dysfunction following halothane anaesthesia is increased in presence of hypoxia, obesity (increased tissue hypoxia and greater storage capacity of halothane), repeated halothane administration at short intervals (less than 3 months), patients with evidence of organ specific autoimmunity and enzyme induction of drugs like phenobarbitone and phenytoin.
      The histological picture is very similar to that of type A viral hepatitis. Clinical features include history of halothane anaesthesia, fever, leucocytosis, bile in urine, a rise in serum bilirubin and jaundice. These features develop on 2nd or 3rd postoperative day. Thus, following halothane anaesthesia, if there is unexplained jaundice and unexplained enzyme abnormalities and pyrexia, a further halothane anaesthesia is contraindicated.
    5. Other volatile anaesthetics: Following enflurane or isoflurane anaesthesia mild hepatic dysfunction may occur. It is mostly non-specific and may be due to decreased hepatic blood flow. But these fluorinated anaesthetics may produce oxidative trifluoroacetyl halide metabolite which may cause liver neoantigens in susceptible subjects. Cross sensitivity may occur between enflurane and halothane. Depending on the magnitude of metabolism, anaesthetic induced hepatitis may occur following enflurane and isoflurane, but on rare occasions. Desflurane has less oxidative metabolism than isoflurane and thus immune mediated hepatitis following desflurane is extremely rare.
  3. Intravenous agents:
    1. Thiopentone: Evidence of liver dysfunction may occur, if given in excess of 750 mg.
    2. Methohexitone causes least depression of liver function in comparison to thiopentone and thiamylal and thus it is preferred to thiopentone in presence of pre-existing liver disease.
    3. Propanidid: In doses 1550 to 7000 mg IV there is biochemical deterioration of liver function. But there is no clinical evidence of liver damage.
    4. Droperidol – fentanyl mixture, diazepam and ketamine: cause no significant alteration of liver function.
  4. Conduction anaesthesia may also have risk of hepatic injury. Spinal anaesthesia reduces hepatic blood flow and may lead to transient elevation liver transaminases. However, it does not cause massive necrosis.
  1. Increased bilirubin load: Blood transfusion, haemolysis and haemolytic diseases, abnormalities of bilirubin metabolism, haematoma reabsorption.
  2. Hepatocellular damage: Pre-existing liver disease, viral hepatitis, sepsis, hypotension, hypoxia, drug induced hepatitis, congestive cardiac failure, halothane hepatitis.
  3. Extrahepatic biliary obstruction: Gallstones, ascending cholangitis, pancreatitis, traumatic damage to bile ducts, inadvertent ligature on hepatic pedicle or bile duct during surgery.
Treatment of Postoperative Jaundice
  1. Hepatotoxic drugs should be withdrawn.
  2. General patient care.
  3. Treatment of hypoxia, hypotension and sepsis.
  4. No specific treatment for viral hepatits. No place of steroid therapy under these circumstances.
  5. Only condition where specific treatment, such as surgery is needed, is extrahepatic obstructive jaundice.
  1. Hepatic blood flow:
    1. Oxygen supply to liver is always low as most part of the blood flowing through liver is venous—portal vein having oxygen saturation only 60 to 75%.11
      Liver has a dual blood supply. Major perfusion comes from portal vein which has little autoregulatory ability. Liver oxygen is mostly derived from hepatic artery and it has significant autoregulatory mechanism. Changes in liver blood flow may be of major significance in liver dysfunction.
    2. During anaesthesia, there is reduction of hepatic blood flow by about 30% of the preanaesthetic level. Liver oxygen consumption is decreased by about 34%. The decrease in hepatic blood flow occurs regardless of the changes of systolic blood pressure.
  2. Hypotension: Hypotension from any cause, as for example, autonomic ganglionic block, spinal, epidural anaesthesia, acute blood loss, etc. reduces the liver blood flow and may cause hepatic hypoxia.
  3. Hypoxia causes hepatic injury and impairs hepatic function.
  4. Hyperventilation reduces liver blood flow.
  5. Hypercapnia may also cause liver damage.
  6. Massive blood transfusion:
    1. Haemolysis: 500 ml of 14 days old stored blood releases about 250 mg of bilirubin for excretion by the liver as 10 to 15 per cent of it undergoes haemolysis. In such cases serum bilirubin is increased and jaundice may appear.
    2. Massive transfusion of blood with acid citrate dextrose solution may cause citrate intoxication. The risk is very much exaggerated in presence of preexisting liver disease as citrate metabolism is impaired. The risk is further enhanced in presence of acidosis as this inhibits the renal excretion of citrate.
    3. Coagulation defect after massive blood transfusion is due to dilution or depletion of platelets, disturbances in coagulation factors, release of fibrinolysins, etc. The danger is exaggerated in presence of liver disease.
    4. Mismatched blood transfusion may induce jaundice.
    5. Viral hepatitis may be transmitted from donor.
  7. Influence of drugs on hepatic microsomal enzymes: Certain drugs can affect the metabolism of microsomes. There may be stimulation of hydroxylation and glucuronylating system and increase in the activities of mitochondrial oxidative enzymes. There may be direct relationship between duration and intensity of drug activity and the speed at which these are metabolised in liver enzymes.12
    When two drugs are given together, chronic administration of one drug may reduce the pharmacological activity of another by stimulating its metabolic inactivation. This action is caused by increasing the amount of drug metabolizing enzymes in liver microsomes – it is usually termed as enzyme induction. Barbiturates, hypnotics, analgesics and tranquillizers may cause such drug interactions. Phenobarbitone stimulates the metabolism of hexobarbitone by liver microsomal enzymes and reduces its hypnotic activity.
    Other drug interactions may also occur. One drug may either increase or even decrease the efficacy of another drug. Sympathomimetic drugs may cause hypertensive crisis in patients with MAO inhibitors. Even the anaesthetic drugs may show some altered pharmacological activities in patients with concurrent drug therapy.
  8. Drug effect in presence of liver disease:
    1. Phenothiazines, antihistaminics, opium derivatives, narcotic analgesics, sedatives and hypnotics – excessive effect may produce coma.
    2. Digoxin – Seventy-five per cent is excreted by liver. It accumulates and increases the toxicity.
    3. Thiazides, frusemide, laxatives like senna, liquid paraffin – may cause potassium loss and thus may provoke encephalopathy.
    4. Local analgesics like lignocaine – action prolonged.
    5. Morphine, pethidine, pentazocine and benzodiazepines may provoke prolonged action and encephalopathy.
    6. Suxamethonium – prolonged action is mostly due to low pseudocholinesterase level.
    7. Tubocurarine, pancuronium – increased doses are needed due to protein binding.
    8. Chlorpropamide – cholestasis.
    9. MAO inhibitors, isoniazid – liver damage.
    10. β blockers, α adrenergic agonists and cimetidine also reduce hepatic blood flow.
Some drugs should be used very cautiously or avoided with active chronic liver disease. These include aspirin, acetaminophen, chlorpromazine, dantrolene, ethanol, halothane, sulphonamides, isoniazid, methyl dopa, nitrofurantoin, propyl thiouracil and so on.13
Clinical features of liver diseases vary widely according to the degree of dysfunction of liver.
  1. Infective hepatitis: Malaise, anorexia, fever, rigor, nausea and vomiting, severe constitutional upset, enlarged tender liver, jaundice. Viral hepatitis may be caused by the virus of hepatitis A, hepatitis B, hepatitis D or hepatitis non-A non-B. Biochemical disturbances are due to bile pigment metabolism and hepatic enzymes.
  2. Chronic liver disease: Indigestion, flatulence, weakness, loss of body weight, muscle wasting, gradual deterioration of health. In chronic liver disease there may be:
    1. Alterations of plasma protein. Albumin level is low with rise of globulin. Ratio of albumin and globulin alters.
    2. Tubocurarine binds with γ globulin and consequently fixed in plasma. This may lead to increased tolerance to tubocurarine.
    3. Prothrombin level becomes low. Bleeding tendency.
    4. Pseudocholinesterase level is low. Suxamethonium should be used with caution.
    5. Diazepam and narcotic drugs may have prolonged effect. Thiopentone in usual clinical doses may not do any harm.
    6. Local anaesthetic drugs like lignocaine and procaine should be used cautiously as the enzymes involving the destruction of local anaesthetics may be interfered in severe liver dysfunction.
  3. Severe liver damage: Hepatic coma, tremor of hands, restlessness, fetid breath due to accumulation of nitrogenous substances and ammonia in blood.
    Several problems may appear in end-stage liver disease. These may include encephalopathy, cerebral oedema, cardiomyopathy, intrapulmonary shunting, thrombocytopenia, and disseminated intravascular coagulation. Kidneys also suffer due to reduced effective plasma volume, increased adrenocorticotrophic hormone, aldosterone activity, water retention and impaired ability to concentrate urine. There are associated hyper- or hyponatraemia, hyper- or hypokalaemia, hypocalcaemia, hypomagnesaemia and metabolic acidosis or alkalosis.
  4. Obstructive jaundice: This is due to failure to excrete bile leading to hyperbilirubinaemia. Chloroform and hepatotoxic agents are to be avoided.14
    1. In such patients fat digestion is impaired. Vitamin K absorption is diminished. Impaired synthesis of prothrombin in liver occurs. Coagulation time is increased and there is tendency of bleeding.
    2. Bradycardia is common in jaundiced patients due to increased bile salts in blood. Suxamethonium and halothane should be used with extreme caution.
  5. Hepatorenal syndrome: It is a form of renal dysfunction that occurs in patients with obstructive jaundice, severe liver disease and portal hypertension. It may be precipitated by diuretic therapy, gastrointestinal bleeding, hypovolaemia or large-volume paracentesis. There is too much sodium resorption by the kidney and urine sodium is less than 10 mEq/lit. Prevention includes careful adequate hydration. Treatment also needs a cautious trial of volume expansion. No specific therapy is reported.
  6. Hepatic encephalopathy: It is a syndrome of disordered consciousness and altered neuromuscular activity seen in patients with hepatocellular failure or a portal-systemic shunt. It may be due to certain toxins such as ammonia, gamma aminobutyric acid and other amino acids, mercaptans and short chain fatty acids, etc. which bypass the liver and enter the systemic circulation in abnormal concentrations in presence of severe hepatocellular failure.
    1. Acute: It may be due to fulminant hepatic necrosis caused by viral hepatitis or drug toxicity (paracetamol).
    2. Chronic: It usually occurs following portocaval anastomosis. Neurological or psychological problems are more than hepatic one.
    3. Acute on chronic: Usually seen in patients with cirrhosis. It may be precipitated by gastrointestinal bleeding, electrolyte disturbances, infection, constipation, sedatives, narcotics, alcohol, anaesthesia, surgery, paracentesis and so on.
Clinical features: Acute illness, apathy, drowsiness, tremor, delirium, coma, permanent brain damage, metabolic alkalosis, hypokalaemia, bleeding. Cerebral intoxication is mostly due to absorbed intestinal contents not detoxicated in liver. In presence of hypoglycaemia there are exaggerated cerebral symptoms.15
Mental state
Grade 1
Confusion, euphoria, altered mood/behaviour
Grade 2
Generalised slowing
Grade 3
Stuporous, but rousable
Delta activity
Grade 4
Comatose, respond to pain
Triphasic waves
Grade 5
Deep comatose
Prognostic Scoring
Score 1
Score 2
Score 3
Gr. 1 and 2
Gr. 3, 4 and 5
Bilirubin µmol/lit.
< 25
> 40
Albumin g/lit.
< 28
Prothrombin time (seconds prolonged)
> 6
Score less than 6 denotes good risk; 7, 8 or 9 denotes moderate risk and more than 10 is poor operative risk.
Treatment of Encephalopathy
  1. Avoidance and correction of predisposing factors.
  2. Protein restriction.
  3. Purgation: Mag sulph enema once or twice daily.
  4. Antibiotics: Poorly absorbed antibiotic, neomycin is drug of choice. It reduces bacterial urease activity and reduces urea production. But neomycin should be used only for short period, because of its toxicity to eighth cranial nerve, kidney and gastrointestinal tract.
  5. Lactulose: This synthetic disaccharide is not hydrolysed or absorbed in intestine but it is metabolised to lactic acid and acetic acid by bacterial action of colon and thus it increases the faecal acidity. It inhibits bacterial urease. The dose should be adjusted as it may cause diarrhoea.
  6. Exchange blood transfusion.
  7. Steroids: Controversial therapy.
  8. Charcoal haemoperfusion.
  9. Haemodialysis.
  10. Liver transplant.
  1. Electrolyte and fluid balance: These patients are mostly fluid overloaded. There may be hypoalbuminaemia, leading to oedema and ascitis and even pulmonary oedema. Secondary hyperaldosteronism will cause sodium retention and hypokalaemia. Diuretics may also lead to potassium loss.
  2. Acid-base status: In hepatic failure a combined metabolic and respiratory alkalosis may occur. This will lead to oxygen dissociation curve shifted to left, thus impairing tissue oxygenation.
  3. Bleeding problems: Production of clotting factors II, VII, IX and X are reduced and there is decreased vitamin K absorption. Production of factor V and fibrinogen are also reduced. Thrombocytopenia may also occur. All these will lead to bleeding tendency. Vitamin K should be given beforehand. Fresh frozen plasma may be needed. DIC is rare, but may be due to tissue thromboplastins released from necrotic liver cells.
  4. Hepatic failure:
    1. Sedative drugs should be used with great care. Diazepam in small doses may be given.
    2. Close metabolic, fluid and electrolyte monitoring.
    3. Hypoglycaemia should be treated with glucose and insulin.
    4. Sodium intake, amino acids, fat emulsion and fructose should be avoided.
    5. Mechanical ventilation may be needed.
    6. For haemorrhagic manifestations: Vit. K, platelet transfusion, fresh frozen plasma. Anticoagulant drugs like heparin are potentially dangerous in liver disease. In presence of DIC, if heparin is used, it should be used with sensible precautions with full laboratory control.
  1. Primary aim should be to prevent further damage, to detect and treat the complications.
  2. Hepatotoxic drugs should be withheld. Avoidance of taking alcohol particularly in addicts is always helpful.
  3. A careful history, physical examination and liver function tests should always be done in preoperative period.
  4. Some measures should be taken to improve the condition of the patient.
    Anaemia should be treated with packed red cell transfusion.
    Hypovolaemia and electrolyte imbalance need adequate correction.
    Coagulopathy may be treated with vitamin K, soluble coagulation factors and platelets. Infection, if any should be controlled. The bowel should be sterilised with neomycin. Lactulose may be needed to inhibit bacterial urease to treat encephalopathy. Ascites may have to be drained to relieve increased intra-abdominal pressure. Previously given scoring system should be used to note the risk, if any.
  5. Premedication:
    1. No premedication in acutely ill patients.
    2. Small dose of diazepam may be helpful. Diazepam is highly protein bound and such patients may have elevated globulin levels. It may have a prolonged effect due to deranged metabolism in liver.
    3. Pethidine and promethazine in small doses may also be used cautiously.
  6. Preoperative vitamin C, vitamin K and glucose may prove useful.
  7. Avoid hypoxia, hypercarbia and hypotension by all possible means.
  8. Monitoring of serum electrolytes, pulse, respiration, body temperature, blood pressure, CVP and ECG is essential.
  9. Avoid hepatotoxic drugs and anaesthetics.
  10. Induction with thiopentone in usual clinical doses is mostly satisfactory. Althesin may be used, but increased doses may be required because of protein binding.
  11. Pancuronium is the relaxant of choice. But atracurium is preferable due to its lack of cardiovascular effects and its elimination is independent of liver and renal function. Tubocurarine and pancuronium may be needed more due to protein binding. Suxamethonium may have prolonged effect. Gallamine and alcuronium undergo no metabolism and these are excreted unchanged in urine.
  12. Avoid repeated halothane anaesthesia.
  13. Controlled ventilation is needed. Blood gas monitoring is essential.
  14. Blood loss should be monitored. Blood transfusion may be needed and it should be given with adequate care.
  15. Prolonged anaesthesia in liver diseases is always bad.
  16. Drugs which depress cardiac output including halothane, enflurane, isoflurane should be used with caution to avoid decreasing hepatic blood flow.
  17. Anaesthesia and surgery may affect the liver function independently. Upper abdominal procedures may hamper the hepatic blood flow significantly. Surgical manipulation and placement of abdominal packs may reduce the hepatic blood flow. Hepatic perfusion may also be deranged by IPPV, hypocapnia, α adrenergic agonists, laparoscopy and surgery in prone position.
  18. Postoperative care should be adequate.
    1. Postoperative monitoring of vital signs is essential.
    2. Postoperative IPPV may be needed.
    3. Analgesic should be used in low doses and with adequate care.
  19. With preexisting liver disease, liver function tests are usually deteriorated following major anaesthesia and surgery. There may be reduction in protein synthesis, raised bilirubin and transaminases. But these changes usually revert to the preoperative state within 5 to 10 days.
  20. Regional and particularly spinal and epidural anaesthetic techniques usually lower splanchnic blood flow and thus may cause further damage to liver. Spinal anaesthesia may reduce hepatic blood flow by even 30% of the normal. Local anaesthetic drugs are also metabolised in liver. So these should be used with sensible precautions.
Obstructive jaundice is due to posthepatic biliary obstructions resulting in failure to excrete bile and leading to hyperbilirubinaemia. Gallstones in the common bile duct are most common and are usually accompanied by pain and pyrexia. It may present as pancreatitis with or without jaundice. Malaise, lethargy, nausea and vomiting, pruritus are common in obstructive jaundice. A palpable gallbladder and jaundice normally indicate obstruction of the common bile duct. Diagnosis is vital, otherwise an unnecessary laparotomy in a case of hepatocellular failure may prove fatal.19
Acute common bile duct obstruction by gallstones produces symptoms similar to those of acute cholecystitis. Repeated attacks of acute cholecystitis may cause a fibrotic gallbladder which is not capable to contract and expel bile.
Murphy's sign: Patient is asked to breathe deeply and then try to palpate gallbladder in sitting position. There is tenderness and catch in breath at the height of inspiration with a palpable mass. It is positive in acute cholecystitis and not in chronic cholecystitis. When the test is performed in lying position it is said Moynihan's method.
Adequate physical examination and history are essential. Other causes of jaundice such as hereditary, haemolytic, cirrhotic, infective or toxic should be taken into account and excluded.
  • Laboratory investigations should include full blood count, blood biochemistry, urine analysis, coagulation studies and liver function tests. X-rays of chest and abdomen and cholangiogram (percutaneous) are also needed. Ultrasound and CAT are done in selected cases.
Haemoglobin percentage may be low due to concealed blood loss or haemolysis. Leucocytosis may be present due to associated cholecystitis and cholangitis. Prothrombin time may be prolonged. A jaundiced patient always carries a risk of renal failure and thus an elevated and rising urea is dangerous and needs urgent treatment.
In obstructive jaundice serum bilirubin is greatly increased. Van den Bergh test is direct positive, serum alkaline phosphatase is more than 30 KA units, serum α2 globulin is increased, and there is mild increase in serum transaminases (SGOT and SGPT). Stool is pale in colour. On urine examination bilirubin is found to be increased, but there is no urobilinogen.
Gallstones can be removed by open cholecystectomy or laparoscopic laser cholecystectomy or dissolution with chemicals or shock wave diathermy.
Preoperative Preparation
The basic care should be taken to preserve hepatic function by maintaining hepatic blood flow and adequate oxygenation.
In obstructive jaundice the higher the serum bilirubin the higher is the risk of renal failure. The risk is intensified in presence of endotoxaemia from infected bile and preexisting renal dysfunction. In such cases hypovolaemia is dangerous as it initiates renal failure. So the patient should not be allowed 20prolonged preoperative fasting. Intravenous fluids in the form of dextrose saline should be started at least 4 hours before surgery. Central venous pressure and urine volume should be monitored. Urine volume should be at least 1 ml/kg/hour. If the urine volume is low, serum bilirubin is over 140 µmol/lit and blood urea is high, 20% mannitol in 200 ml should be given in IV infusion. Some prefer frusemide to maintain diuresis, but the circulating fluid volume should be maintained well all the while.
In such patients fat digestion is impaired and vitamin K absorption is diminished resulting in impaired synthesis of prothrombin in liver. Parenteral vitamin K should be given at least 24 hours before surgery to get the maximum effect.
Renal damage is more likely to occur in presence of endotoxaemia, so a suitable antibiotic preferably a cephalosporin should be started well before anaesthesia and surgery.
Bradycardia is common in jaundiced patients due to increased bile salts in blood. Atropine should be given in premedication particularly when suxamethonium or halothane is to be used. Pethidine may also be given as it constricts the sphincter of Oddi less than other agents particularly morphine. Fentanyl can also produce spasm of choledochoduodenal sphincter and increase common bile duct pressure. The spasm can impair the free passage of contrast medium to duodenum and misguide to perform sphincteroplasty and diagnose stones in common bile duct. Narcotics, whenever given, should be used in a lower than usual dosage as there may be derangement of drug metabolism in presence of liver dysfunction.
Preoperative physiotherapy may be beneficial to optimise pulmonary function and to familiarise the patient in his postoperative treatment.
Anaesthetic Management
The primary aim should be to maintain the hepatic and renal blood flow as far as practicable for which hypoxia, hypercarbia and hypotension should be avoided. Over and above normocarbia should be maintained and the patient should be well hydrated. Monitoring of pulse, blood pressure, CVP, ECG and urine volume is essential in perioperative period.
Induction of anaesthesia may be done with thiopentone in usual clinical doses. Hypotension during induction needs prompt infusion of fluid. Pancuronium seems to be the relaxant of choice as it maintains the cardiovascular stability. Atracurium is also preferred as its elimination is 21independent of liver and kidney functions and it lacks major cardiovascular effects. Suxamethonium is better avoided in presence of bradycardia.
Ventilation should better be controlled and normocapnia should be maintained as far as practicable. Halothane and other volatile anaesthetics (except chloroform) are not readily contraindicated but care must be taken not to cause any cardiovascular depression. The presence of hyperbilirubinaemia may increase the intrapulmonary shunt, so inspired oxygen concentration should better be increased to 40% or above. Intravenous fluid therapy is most vital to maintain adequate fluid balance and urine volume.
Neuromuscular block should be well reversed prior to endotracheal extubation. Oxygen should be given in early postoperative period. Postoperative analgesia may be needed, but parenteral narcotic analgesics should be used in low dosage with great caution. Regarding antibiotic therapy aminoglycosides should be avoided for their nephrotoxic effects.
Anaesthetic management of laparoscopic cholecystectomy is mostly similar to those for other laparoscopic operations. Several important points should be taken into account.
  1. Usually pneumoperitonium is done by insufflation of peritoneal cavity with carbon dioxide. These may increase the intra-abdominal pressure abruptly and may impair the ventilation and venous return.
  2. Reverse Trendelenburg position may be helpful for better visualisation of the operation site and may improve machanical ventilation of the lungs. But it may also impair venous return.
  3. Risk of venous carbon dioxide embolism is always there and thus monitoring of end tidal carbon dioxide is often helpful.
  4. Intraoperative decompression of the stomach is needed through nasogastric tube to avoid the risk of accidental puncture of viscera.
  5. Loss of haemostasis or injury to hepatic artery or viscera may need prompt laparotomy.
Portal vein is formed by the union of superior mesenteric vein and splenic vein. About two-third of hepatic blood flow and half of the oxygen supply to 22the liver are provided by the portal vein. The normal portal venous pressure is 5 to 10 mm Hg. Portal hypertension is defined when the pressure is above 12 mm Hg. Most common cause of portal hypertension is cirrhosis of liver. In cirrhosis, there is obstruction of portal blood flow leading to a rise of pressure in the vessels proximal to the point of obstruction. Here the portal vascular bed is distorted and diminished due to hepatic fibrosis with compression of portal venules and also by compression by regenerative nodules. Some of the portal venous blood is diverted into collateral venous channels and some bypasses the liver cells and is shunted directly into the hepatic vein.
Common clinical features of portal hypertension are oesophageal varices, prominent collateral veins radiating from the umbilicus, dilated rectal veins and hepatomegaly with or without splenomegaly. Gastro-oesophageal varices are predictable complication of portal hypertension. Chronic bleeding from the varices may lead to anaemia. Severe haemorrhage may need blood transfusion, balloon tamponade or sclerotherapy. There are weight loss, weakness, lethargy and anorexia. Weight gain and swelling of abdomen and legs may indicate ascitis. Ascitis causes decreased plasma osmotic pressure due to low serum albumin level, increased resistance to blood flow through portal vein and increased secretion of antidiuretic hormone. Jaundice is not uncommon.
Hepatocellular failure produces a hyperkinetic circulatory state with tachycardia, high cardiac output, flushed extremities, bounding pulse, capillary pulsation and systolic murmur. These patients may have intrapulmonary shunts, pulmonary vasodilatation, pulmonary infection, pleural effusion and pulmonary oedema. Thus, a decompensated cirrhosis is associated with a reduced PaO2 and there may be cyanosis and dyspnoea. Pneumonia is common in alcoholic patients. There may be suppression of immune defense mechanisms in case of chronic alcoholics. Chronic cirrhosis has a close association with diabetes mellitus. There may be signs of encephalopathy due to bacterial overgrowth from bacterial metabolic wastes. The patient may be anaemic due to gastrointestinal blood loss from oesophageal varices. All these have varied implications in anaesthetic management of such cases.
Investigations should include full blood count, blood biochemistry, urine analysis, liver function tests, ECG, clotting studies, chest X-ray, endoscopy, liver biopsy and EEG. Blood gas analysis may also be indicated in severe cases.23
Risk of surgery should be determined according to Child's grouping and scoring system.
Preoperative Preparation
The patient may be anaemic, tachycardiac, hypotensive and dyspnoeic. There may be considerable reduction of circulating blood volume and hypoproteinaemia. All these should be considered and treated accordingly. Fresh blood transfusion in such cases may be helpful. It will increase the oxygen carrying capacity and restore the plasma proteins and deficient clotting factors. Fresh blood contains less ammonia than stored blood and thus lessens the dangers of hepatic coma.
Presence of jaundice makes the prognosis grave. The hepatorenal syndrome is exaggerated by sepsis, haemorrhage, hypotension, hypoxia and surgery. Cirrhosis of liver is usually associated with a decrease in renal blood flow and glomerular filtration rate.
Ascitis causes abnormal binding and metabolism of drugs, abnormal excretion of electrolytes, poor renal function and splinted diaphragmatic movement. Huge ascitis reduces the tidal volume and vital capacity. Preoperative paracentesis may have to be done though it carries a high risk of precipitating both renal and hepatic failure and encephalopathy.
Preoperative treatment of ascitis by bedrest and diuretics may also be helpful. Weight loss should be gradual and should not exceed 0.5 kg/day. Careful monitoring is essential, otherwise central circulating volume will be much reduced and there is a high risk of developing a diuretic induced uraemia.
In presence of signs of encephalopathy, magnesium sulphate enemas, oral lactulose and oral neomycin should be given to alter and reduce bacterial flora of the gut.
Premedication: Narcotic analgesics may precipitate encephalopathy. Small doses of pethidine and promethazine can be used. Atropine should be used cautiously, if the patient is tachycardiac.
Anaesthesia: The maintenance of adequate blood pressure is of paramount importance as the cirrhotic liver receives most of its blood supply from the hepatic artery. Hypoxia and hypovolaemia should be avoided to minimise any disturbance of kidney and liver perfusion. These patients tolerate blood loss badly.24
After preoxygenation, anaesthesia may be induced with small doses of thiopentone. Large doses should be avoided as it may worsen encephalopathy. Increased binding to globulins and enzyme induction may lead to an increased dose requirements. Light general anaesthesia with nitrous oxide, oxygen and added small percentages of enflurane may be helpful. Ventilation should be assisted or controlled. Suxamethonium can be used but its action may be prolonged due to low pseudocholinesterase level. The response to nondepolarizing relaxants is not always predictable due to abnormal protein binding and possible increased sequestration in liver. Pancuronium and atracurium may be used satisfactorily in cirrhotic patients.
Careful monitoring of pulse, blood pressure, CVP and ECG is essential. Cirrhotic patients have low glycogen reserve, so their blood glucose needs checking frequently. Nasogastric tubes should be passed very carefully as it may injure oesophageal varices.
Postoperative care: Adequate oxygenation and hydration are needed. Hypoxia and hypotension are to be avoided. Postoperative analgesia may be needed. Parenteral analgesics should only be given in small incremental doses. Chest infection is common, so proper antibiotics and early physiotherapy are recommended.
Following portocaval anastomosis hepatic coma and fulminant hepatic and renal failure may occur. This should be detected early and treated accordingly.
Special Note
Some causes of huge hepatomegaly: Hepatoma, metastitis in liver, polycystic liver, fatty liver, chronic malaria, chronic kala-azar, Hodgkin's disease.
Tender liver: Acute hepatitis, congestive heart failure, liver abscess, cancer liver.
Soft liver: Congestive heart failure, acute hepatitis, fatty liver, acute malaria.
Firm liver: Cirrhosis of liver (sharp and irregular margin), chronic malaria, chronic kala-azar.
Hard liver: Carcinoma liver, metastasis in liver.25
Hepatosplenomegaly: Chronic malaria, chronic kala-azar, enteric fever, thalassaemia, chronic myeloid leukaemia, lymphoma, tropical splenomegaly syndrome, viral hepatitis, cirrhosis of liver, myelofibrosis etc.
Hepatosplenomegaly with ascitis: Portal hypertension, lymphoma, chronic myeloid leukaemia.
Hypersplenism: Primary or secondary due to connective tissue disorders, lymphoma, cirrhosis of liver or congestive splenomegaly. Characteristic features are splenomegaly, pancytopenia, normal or hypercellular bone marrow and reversibility by splenectomy.
Evidence of porto systemic anastomosis
  1. Lower end of oesophagus – Oesophageal varices: Left gastric vein, short gastric vein and posterior gastric vein (portal) communicate with intercostal veins, diaphragmo-oesophageal vein and azygos minor vein (caval).
  2. Internal haemorrhoids – Superior rectal vein (portal) communicates with middle and inferior rectal veins (caval).
  3. Around the umbilicus – Caput medusae.
Liver transplantation is now-a-days much popular for patients with end-stage hepatic failure and for management of hepatoma, biliary tract tumour or genetically determined metabolic disorders. Life expectancy can be greatly improved in such cases.
Various anaesthetic problems may be encountered in tackling such patients.
  1. Severe hepatic dysfunctions are often present.
    1. encephalopathy
    2. anaemia
    3. ascites
    4. oliguria
    5. coagulation disorders: thrombocytopenia, DIC
    6. electrolyte disturbances: hypokalaemia, hypocalcaemia
    7. metabolic disorders—glucose intolerance
    8. congestive cardiac failure
    9. hypoxaemia.
  2. Whenever decided, transplantation should be done as early as possible urgently and enough time may not be available to optimise the medical conditions.
  3. Cadaver livers are used for transplantation. Perfusion technique is often helpful to procure it from long distances.
  4. Extensive monitoring is needed during operation.
    1. Invasive monitoring of arterial blood pressure and cardiac filling pressure.
    2. Large bored catheter placement is helpful for fluid replacement.
    3. Massive blood and fluid replacement may be needed.
    4. Various coagulation changes are common. Thrombocytopenia, dilutional coagulopathy, fibrinolysis etc. may occur.
    5. Severe haemodynamic changes may also occur particularly during reperfusion (Reperfusion syndrome).
    6. Decreased venous return occurs during clamping of inferior vena cava. Cardiac inotropics like dopamine or sympathomimetic drugs may be needed to tackle the situation.
    7. Hypothermia may occur and this should be guarded adequately.
    8. Metabolic acidosis is common.
    9. Hyperkalaemia.
    10. Blood glucose monitoring is essential.
    11. Oliguria, if present should be due to either renal dysfunction or hypovolaemia.
    12. The clamping of abdominal aorta and suprahepatic inferior vena cava dictates the placement of arterial and venous access catheters above the diaphragm.
Anaesthetic Management
  1. Ketamine may be used for induction of anaesthesia.
  2. Suxamethonium or mivacurium may have prolonged duration of action due to low pseudocholinesterase level.
  3. Volatile anaesthetic agents particularly isoflurane may be used for maintenance of anaesthesia.
  4. Nitrous oxide is better avoided as it may cause bowel distension and increases the risk of venous air embolism at the time of revascularisation of the liver. Nitrous oxide may also affect pulmonary vascular resistance in such patients with co-existing pulmonary hypertension.
  5. Opioids and muscle relaxants should be used carefully considering the hepatic or renal routes of elimination of drugs. Atracurium may be the muscle relaxant of choice in such cases.
  6. Mechanical ventilation should be proper and adequate all the time during anaesthesia and even in early postoperative period.
  7. Postoperative liver function tests should be done at short intervals as the abnormalities may signal the rejection of graft.