ANAESTHESIA AND LIVER DISEASE

1. ANAESTHESIA AND LIVER DISEASE Dr.Pratheeba Durairaj ,M.D,D.A, HAPPY 2009

2. Liver Functions • The liver conjugates bilirubin, produced from the degradation of the haemoglobin - water-soluble form of bilirubin is then excreted into the bile ducts • The bile salts produced by the liver are passed to the gut - necessary for the absorption of the fat-soluble vitamins A, D, E and K. • Synthesis of proteins - most clotting factors, albumin. • Lipid metabolism - cholesterol and triglycerides synthesised here. • Carbohydrate metabolism - synthesis and breakdown of glycogen . It stores glycogen and releases glucose into the blood when the blood glucose falls for any reason. • Biotransformation of drugs either by oxidation or conjugation - render them water-soluble - more easily excreted. 

3. Impaired liver function Direct effects • Hypoglycemia, Lactic acidosis , Hyper metabolism, Azotemia and Impaired urea synthesis. • Jaundice appears when serum bilirubin exceeds 35 µmol/l • Defects in cholesterol metabolism together with intra-hepatic cholestasis may lead to production of poor quality bile and malabsorbtion of fat and fat-soluble vitamins. • Reduced synthesis of proteins such as albumin, clotting factors, thyroid binding globulin and pseudo-cholinesterase. • Impaired hormone biotransformation, reduced production of modulator proteins and reduced protein binding lead to increased circulating levels of hormones such as insulin, thyroxine, T3, aldosterone and oestrogen

4. Indirect effects Cardiovascular changes • Vasodilatation and vascular shunting are almost invariable in ESLD. • Low systemic vascular resistance (SVR) results in high cardiac output and high mixed venous oxygen saturations • Intrapulmonary & arteriovenous shunting • Pulmonary hypertension may develop • Tachycardia, bounding pulse ,Ejection systolic murmur

5. Pulmonary changes • Pulmonary problems are both vascular and mechanical. • Hepato-Pulmonary syndrome – triad of end stage liver disease, A-a gradient >2 kPa , intrapulmonary vascular dilation • Impaired pulmonary function in absence of cardiopulmonary disease • Impaired hypoxic vaso-constriction and ventilation perfusion mismatch lead to arterial desaturation and clubbing if chronic. • Cyanosis ,dyspnoea , platypnea, orthodeoxia [desaturation pronounced in upright position relieved by recumbency ] • Pleural effusions together with ascites can cause considerable mechanical embarrassment of respiration and a reduction in functional residual lung capacity.

6. HEPATORENAL SYNDROME • 􀂄 Low GFR • 􀂄 Low renal blood flow • 􀂄 No other cause for renal failure • 􀂄 “Functional renal failure” • Symptoms – water retention, Azotemia, hyponatremia, & oliguria

7. Hepatorenal failure • Causes may be Pre and peroperative dehydration Hypovolaemia Falls in renal blood flow during surgery, Direct effect of the excess conjugated bilirubin on the renal tubules or possibly an increased absorption of endotoxin from the gut. • Not a major risk in patients with Prehepatic jaundice. 

8. Managementof Hepato renal syndrome • Avoid it developing by ensuring adequate hydration and a urine flow of at least 50mls/hr in the average adult patient. • In moderately elevated bilirubin - simple fluid loading for 12 hours before surgery using 0.9% NaCl and during the operation. If the urine output is not maintained - Mannitol 10% • Bilirubin greatly elevated (>140 micromols/litre), - intravenous fluids during the 24 hours before surgery and for 36 hours postoperatively. Mannitol 10% 0.5-1g/kg - prior to surgery without making the patient dehydrated as a result of an over-zealous diuresis.

9. Neurological problems • Mechanisms leading to deepening encephalopathy -incompletely understood. • Due to accumulation of neurotoxic compounds penetrating an impaired blood-brain barrier. • Symptoms can occur in chronic as well as in acute disease, may be rapid in onset • Precipitated by a gastrointestinal bleed, dietary protein overload or sepsis. • Somnolence can be exacerbated by sedative drugs and narcotics. • Rapid correction of hyponatraemia can lead to osmotic demyelination and central pontine myelinolysis and should be avoided

10. HAEMATOLOGICAL PROBLEMS • Anaemia may be the result of nutritional deficiency, toxic bone marrow depression or gastrointestinal bleeding from varices or erosions. • Coagulation defects arise from thrombocytopenia, platelet dysfunction and decreased levels of circulating clotting factors. • Clotting factor levels fall because of impaired synthesis, vitamin K malabsorbtion and intravascular consumption. • The short half-life of clotting factors means that INR or Prothrombin Ratio (PTR) can reliably be used to evaluate residual hepatic function. • Treatment –Vit K ,FFP

11. GASTROINTESTINAL SYSTEM • Rupture of oesophageal varices • Vassopressin & octreotide –reduce portal hypertension • Susceptibility to infection - increased Drug disposition • Cholestasis will reduce absorption of fat-soluble drugs after oral administration. • Compartment changes and altered protein binding will affect volume of distribution, clearance and re-distribution. • Patients with liver dysfunction may be particularly sensitive to opiates and benzodiazepines due to altered end-organ sensitivity

12. Effect of hepatic dysfunction on anaesthetics • ↓ Albumin -increased free fraction • Altered volume of distribution [Ascites & increased total body water compartment], • Reduced metabolism –alters drug pharmacodynamics Opiods - • Morphine ,pethidine -↑ ↑ respiratory depression & sedation Sedative /hypnotic drugs • Benzodiazepines – prolonged NDMR • Prolonged action for vecuronium and pancuronium DMR • Decreased serum cholinesterase activity

13. The Effect of Anaesthetics on Liver Function VOLATILE AGENTS • Halothane -↓ HABF/PBF, disturb HABR [hepatic arterial buffer response] • Sevoflurane ,isoflurane maintain HABR • SEVO > ISO > DES > HALO IV ANAESTHETICS • Thiopentone /etomidate -↓THBF • Propofol - ↑THBF –splanchnic vasodilator • Ketamine – no effects REGIONAL ANAESTHESIA • High epidural may reduce THBF

14. Effect of General Anaesthesia on liver functions in patients with preexisting liver diseases • Indian Journal of Anaesthesia. 1989 Apr; 37(2): 61-6 • ABSTRACT: Effects of anaesthetics on liver functions were studies in 13 patients having no liver disease (group I) and 11 patients having liver disease (group II). • Serum cholinesterase increased significantly in both the group. Rise in SGOT levels was significant only in group I, who had greater surgical trauma and not in the other group of patients (group II). • Significant decrease in total serum proteins was seen on different postoperative days in group I but only on 5th postoperative day in group II. • It was concluded that presence of liver disease does not increase the adverse effect of anaesthesia on liver function and that surgical trauma is more important than anaesthesia in producingliver dysfunction.

15. Jaundice Hepatomegaly Spider Naevi Splenomegaly Scratch Marks Ascites Palmer Erythema Dilated Abdominal Veins Peripheral Oedema Finger Clubbing Testicular Atrophy Bruising Gynaecomastia Confusion/Coma  Signs of Liver Disease

16. Jaundice Prehepatic jaundice [haemolysis] • Massive intravascular haemolysis - as in some forms of malaria or in sickle cell anemia • Hepatocellular function is normal but overwhelmed - increased unconjugated bilirubin • Intact Protein and carbohydrate metabolism • No reduction in the absorption of Vitamin K or production of clotting factors. Hepatocellular jaundice • Hepatitis or Cirrhosis • decreased protein synthesis, signs of delayed clotting, and even encephalopathy.

17. CONTD… Obstructive Jaundice • Biliary obstruction - from a stone in the common bile duct, pancreatic tumour or ascending cholangitis • Hepatocellular function is normal • Excess plasma bilirubin is chiefly conjugated - excreted in the urine which becomes dark. • Stools are pale as a result of poor lipid absorption. • Protein synthesis is normal • Vitamin K dependant clotting factors reduced as the absorption of vitamin K is dependent on the excretion of bile salts into the small intestine → clotting time prolonged parenteral vitamin K.

18. Renal impairment in Jaundice • Release of endotoxins into systemic circulation following biliary obstruction – renal failure • Prevention - in high sr.bilirubin levels – percutaneous drainage of biliary tree under antibiotic cover - pre op oral bile salts -↓ post op RF

19. Liver Function Tests • Indication of severity, help to differentiate between prehepatic, hepatocellular and obstructive jaundice. • Jaundice - sign of an elevation of serum bilirubin. • Protein and albumin levels are normal in prehepatic or obstructive jaundice, low values indicate hepatocellular damage. • clotting - Prothrombin Time • An elevated INR may indicate impaired synthesis of clotting factors due to hepatocellular damage or malabsorption of vitamin K due to biliary obstruction.

20. Contd… • Prothrombin time[ half life - 6 -12 hrs ] – best indicator than Albumin [ half life – 24 -48 days] • Alanine Transaminase (ALT) and Aspartate Transaminase (AST) are enzymes that are released into the circulation by damaged hepatocytes. Raised levels indicate hepatocellular damage. • AST can also be elevated in other circumstances such as myocardial infarction • Alkaline Phosphatase (ALP) is an enzyme localized near the bile cannaliculi and is elevated in biliary obstruction. Not specific to hepatobiliary disease,[ raised in malignant bone disease]. • An accompanying rise in Gamma glutamyl Transferase (Gamma GT) suggests that the ALP is from the liver.

21. Contd… • Glutathione – S – transferase –to assess damage due to anaesthetics • ALP –Early in biliary obstruction • γ - Glutamyl trans peptidase – rises after alcohol & drug induced liver damage • Plasma glucose should be measured

22. Risk and severity scoring • In 1964, Child and Turcotte classified risk for patients with liver cirrhosis undergoing porto-caval anastomosis for management of portal hypertension. • Pugh et al at King's College Hospital published a severity scoring system for patients undergoing oesophageal transection for bleeding oesophageal varices. • The two systems have been amalgamated and provide a disease severity assessment based on two clinical and three laboratory variables

23. PUGH‘S MODIFICATION OF CHILD GRADING POINTS : 5- 6 – class A [5% Mortality] , 7 -9 –Class B [10% mortality], 10 -15 –Class C [50% mortality]

25. Surgery in patients with liver dysfunction • The Child-Pugh classification is a useful method of staging the progress of liver decompensation. • Limited predictive value in anaesthesia and surgery • Group A patients are lower risk and with sufficient care can be considered as candidates for most types of surgery. • Group B patients – acceptable but correct abnormalities • Group C patients present an extremely high operative risk - surgical procedures in these patients should be avoided if possible.- only emergency or life-saving procedures should be undertaken

26. Preoperative assessment • Type and extent of liver disease • Extra hepatic effects • Risk assessment • Patients general condition- hydration ,nutrition • Associated co-morbid conditions • LFT • Consent • Premedication-short acting temazepam in absence of neurological impairment orally –avoid intramuscular injections • H2 receptor antagonists • Preop Vit K ,optimal hydration

27. PREOP INVESTIGATIONS • Hematological –Hb , Platelet count,WBC Coagulation profile • Metabolic – sr. glucose ,urea ,creatinine electrolytes • Cardio respiratory – chest x-ray,ECG ,PFT, ABG • Liver function – sr.bilirubin,albumin,liver enzymes

28. Pre-op risk factors associated with postoperative mortality • Serum albumin <3g/L • Serum bilirubin >50 µmol/L • PT >1.5 s over control • Presence of infection • WBC > 10,000 • Treatment with more than two antibiotics • Presence of Ascites • Malnutrition • Emergency surgery

29. Anaesthetic Technique • Avoid hypotensive techniques—intra hepatic necrosis • High conc of oxygen -- - due to intrapulmonary shunts • Avoid hypotension & hypoxemia • Meticulous fluid balance – Ascites – may lose a large amount of fluid rapidly Concentrated albumin solutions –to correct hypoproteinemia Fresh blood –to prevent hypocalcemia due to reduced metabolism of preservatives FFP 12 - 15 ml/Kg –Correct dilutional coagulopathy • 1 unit of FFP for every 1 unit of packed cells or 250 ml of 0.9% saline or colloid [500 ml of FFP - ↑ Clotting factors by 20% ] • Maintenance of temperature

30. Monitoring • Monitoring of temperature • Coagulation status should be monitored –platelet count ,fibrin degradation products , prothrombin time , activated clotting time, partial thromboplastin time Thromboelastography has been used as a tool in liver transplantation • Repeated BP cuff inflation –may lead to bruising in patients with altered haemostatic function • Insertion of Intra arterial line – care to prevent haematoma • Jugular route is preferred in CVP monitoring • Oximetry • Urine output • Blood loss • Monitor ionized calcium

31. DRUGS • Thiopentone – intrinsic clearance delayed but recovery not delayed because of redistribution • Alcoholic cirrhosis – larger dose of thio – cross tolerance • Halothane and enflurane reduce hepatic arterial flow (vasodilatation, negative inotropic effects) • Isoflurane increases hepatic blood flow [preferred]

32. NEUROMUSCULAR BLOCKING AGENTS • Reduced plasma pseudo cholinesterase activity • Prolonged action- vecuronium , pancruonium[1.6 fold] Decreased biliary excretion Increased volume of distribution –larger initial doses • 􀂄 Recommended Atracurium – metabolism independent of liver and kidneys • 􀂄 For transplantation – long acting agent such as doxacurium

33. OPIODS & SEDATIVES Narcotics • Reduced metabolism of morphine and pethidine • Prefer fentanyl • Remifentanyl - ideal 􀂄 Benzodiazepines • 􀂄 Diazepam - prolonged half life • 􀂄 Oxazepam and lorazepam preferrred –metabolised by glucuronidation without liver requirement

34. ? Regional Anaesthesia • Contraindicated if PT >2.5 s above control, platelet count < 50,000 /cu.mm, bleeding time >12 mts • Spinal and epidural anaesthesia carries the risk of epidural haematoma and paralysis if there is abnormal clotting but there are otherwise no special precautions. • The half-life of lignocaine is prolonged in liver failure but this is not significant when used in regional anaesthesia.  • LA dose diminished in presence of Ascites

35. Canadian Journal of Anesthesia, Vol 45, 452-459, Obstetrical anaesthesia for a parturient with preeclampsia, HELLP syndrome and acute cortical blindness • A 39-yr-old woman, with three past uncomplicated pregnancies presented at 33 wk with acute cortical blindness. • Based on clinical and laboratory assessment, a diagnosis of preeclampsia with HELLP syndrome was made. • A CT scan of her head demonstrated ischaemic lesions of her basal ganglia, extending superiorly to involve both posterior parietal and occipital regions. • Infusions of magnesium sulphate and hydralazine were started and an urgent Caesarean section was performed under subarachnoid anaesthesia after insertion of an arterial line and intravenous hydration.

36. Contd… • The course of anaesthesia and surgery was uneventful and she delivered a live 1540 g female infant. • By the following morning, she had recovered some vision and visual recovery was complete by 72 hr postpartum. • Her postoperative course was uneventful • CONCLUSION: Provided that it is not contraindicated because of prohibitive risk to the mother, regional anaesthesia has particular advantage in these patients. • In particular, the use of spinal anaesthesia, which has been discouraged by some for this patient population, should be re-evaluated.

37. Postoperative management • Oxygen enriched air • Major surgery – elective post operative ventilation • Replace blood loss • Maintain adequate urine output • Dopamine and inotropes should be continued. • The principle complications are likely to be continued bleeding, sepsis and hepatic decompensation

38. Peri-operative considerations in Child-Pugh A patients • Pre-operative Aetiology of condition - virology, Drug idiosyncrasy Blood count and platelets Clotting screen Assess renal function Previous anaesthetics • Per-operative Consider drug bio-availability issues ? Avoid drugs excreted via liver Regional techniques acceptable if clotting normal • Post-operative Monitor for post-operative hepatic decompensation Possible prolonged duration of action in opiates HDU / ITU care

39. Child-Pugh Group B/C patient undergoing major surgery • Previous upper abdominal surgery, portal hypertension and coagulopathy dramatically increase the potential for per-operative blood loss • 8-12 units of blood, together fresh frozen plasma and platelets should be available. Pre-medication • Sedative premedicants should be avoided in the encephalopathic patient. • Other drugs may be needed pre-operatively and include antibiotics and H2 receptor antagonists. • The oral or intravenous route used - intramuscular injections should be avoided. • Coagulopathy may require correction with fresh frozen plasma and platelets and renal replacement therapy may need to be considered.

40. Per-operative considerations • Regional techniques -- considered carefully - coagulopathy , epidural varices can pose an additional risk. • Vascular access with a multi-lumen central venous catheter together with at least one large bore central line • Monitoring of arterial and central venous pressures is mandatory. • Pulmonary artery, pulmonary capillary wedge pressure and cardiac output measurements may be necessary in the sick patient. • Trans-oesophageal echocardiography and volumetric haemodynamic monitoring / pulse contour analysis can provide significant additional information for the strategic management of these patients.

41. CONTD… • Coagulation and fibrinolysis are major concerns. • The potential for large volume blood replacement means that temperature should be measured and a fluid warmer and warming mattress used. • Regular per-operative estimation of INR/PTR may be necessary - thromboelastography provides useful intra-operative evaluation of coagulation. • Blood conservation - considered • Preservation of hepatic function - N-acetylcysteine (NAC) is a sulphur-containing antioxidant - benefit patients with fulminant hepatic failure. NAC appears to improve oxygen delivery and consumption, and reduce base deficit. • Renal Function - Dopamine may be useful

42. Bleeding oesophageal varices • Bleeding oesophageal varices - life-threatening complication of - often occur against a background of abnormal clotting, thrombocytopenia, encephalopathy and Ascites. • Overall mortality is 30%. The principles of anaesthetic management • Protect the airway. • Establish good vascular access. • Volume replacement - colloid, blood, fresh frozen plasma and platelets. Avoid saline. • Check / correct clotting. Give Vitamin K, correct fibrinolysis and review blood chemistry.

43. Intoxicated Alcoholic Patients • Requires less anaesthetic –additive depressant effect of alcohol & anaesthetics • Ill - equipped to withstand stress & Acute blood loss • Alcohol decrease the tolerance of brain to hypoxia • ↑ Risk of regurgitation & aspiration - alcohol ↓tone of lower oesophageal sphincter & slows gastric emptying • Alcohol Interferes with platelet aggregation • Causes ↑conc. of plasma catecholamines → ? Intraoperative dysarrhytmias

44. Patient factors Congenital hemolytic disorders Acquired hemolytic disorders Pre existing liver disease Coagulopathy Gilberts syndrome Sepsis Perioperative factors Anaesthetic induced ↓HBF Bleeding Hypotension Blood transfusion Biliary tree trauma Viral hepatitis Drugs Halothane ,antibiotics Nonsteroidal agents POSTOPERATIVE JAUNDICEMild – 17%, marked - 4%

45. POSTOPERATIVE JAUNDICE • Extravascular break down of haematoma [1 ltr] -5000mg Bilirubin • 500ml of blood transfusion – contains 250 mg bilirubin • Intravascular destruction of RBC can occur in G6P-dehydrogenase defeciency, cardiopulmonary bypass, Artificial valves, sickle cell disease, multiple blood transfusions • Delayed transfusion reactions – hemolysis –postop jaundice • Biliary obstruction due to surgery -↑bilirubin & ↑alkaline phosphatase within 3 days of surgery

46. Contd… • Postop cholecystitis/pancreatitis may follow non biliary surgery 3- 30 days post op • Post operative intrahepatic cholestasis [benign] - associated with multiple blood transfusions, hypoxia ,hypotension - ↑bilirubin & ↑alkaline phosphatase within 2-7 days of surgery –resolution in 3 weeks Management • Prevention is the best treatment • Avoid precipitating factors

47. Halothane Hepatitis • The incidence is 1:7000-30,000 halothane anaesthetics - higher in women, the middle aged and the obese • Rarer in paediatric patients and with the newer volatile agents. • Commonest iatrogenic cause of fulminant hepatic failure • “Unexplained liver damage within 28 days of halothane exposure in previously normal patient” – idiosyncratic reaction • Clinical features : malaise, anorexia,fever within 7 days ,jaundice within days to 4 weeks

48. Halothane Hepatitis DIAGNOSIS • Serum antibodies that react with specific liver microsomal proteins that are altered by trifluroacetyl chloride metabolite of halothane • Gross rise of Transaminases [500 -2000 u/l] Risk factors • High - recent previous exposure [ 78 %] previous adverse reaction • Uncertain - obesity Female [1.6 :1 ] Drug allergy [ 15 %] Family history Lymphocyte sensitivity to phenytoin

49. Contd… • The cause not fully established - multifactorial - ? possible immunological cause . • Immune sensitization to trifluoracetylated proteins produced by Cyt P450 2E1 in genetically predisposed subjects • Reduced hepatic blood flow and hypoxia are also to blame • Related to the degree of metabolism of the volatile agent, so toxic metabolites may be involved. • The onset time of the jaundice is shorter with increasing numbers of exposures to halothane. • Nevertheless, enflurane and isoflurane are associated with hepatic dysfunction, albeit apparently at lower rates than halothane. WHO database holds 225 and 159 reports respectively.

50. Halothane exposure guidelines Avoid Halothane if • Within at least 3 months of a previous exposure • Previous adverse reactions -jaundice or pyrexia • Family history of hepatic reactions to halothane. • Pre - existing liver disease • Adverse reactions to Other volatile anaesthetic agents.