Hepato-Billiary system & anesthesia by Dr.Liyakhath.

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1.Effect of Anesthetics on Hepatic Function.2.Effect of Hepatic Dysfunction and Hepatobiliary Disease on Anesthetic Drug Pharmacokinetics.3.Risk Factors for Postoperative Hepatobiliary Complications. : 

1.Effect of Anesthetics on Hepatic Function.2.Effect of Hepatic Dysfunction and Hepatobiliary Disease on Anesthetic Drug Pharmacokinetics.3.Risk Factors for Postoperative Hepatobiliary Complications. MODERATOR : DR.BINDU 1

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HEPATIC PHYSIOLOGY ; OVERVIEW. Liver is the largest internal organ and largest gland in the human body. High regenerative capacity. The acinus is the functional micro vascular unit of the liver. It has three circulatory zones, defined by hepatocellular proximity to the portal axis. Liver is a epicenter for metabolism of various drugs, including anesthetics. Dedicated set of Cytochrome P-450 enzyme system. 2

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Hepatocytes of zone 3, which have the highest density of cytochrome P450 proteins, are the most susceptible to injury from drug metabolism, oxidative stress, severe hypotension, or hypoxia. 3

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Splanchnic Circulation The vasculature of the splanchnic organs can retain up to 15% of the total blood volume rendering it the largest physiologic reservoir of whole blood in the human body. Hepatic Blood Flow   The liver receives roughly 25% of the total cardiac output (1 mL of blood per 1 g of liver) via a dual vascular supply. 5

Dual blood supply.Hepatic artery-25% (50% O2 delivery)portal vein-75% (50 % O2 delivery). : 

6 Dual blood supply.Hepatic artery-25% (50% O2 delivery)portal vein-75% (50 % O2 delivery).

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Regulation of Hepatic Blood Flow.. Intrinsic Regulation. Hepatic Arterial Buffer Response. a. With an intact HABR, changes in portal venous flow cause reciprocal changes in hepatic arterial flow. b. The HABR mechanism involves the synthesis and washout of adenosine from periportal regions. c. Various disorders (e.g., endotoxemia, splanchnic hypo perfusion) may decrease or even abolish the HABR and render the liver more vulnerable to hypoxic injury. 7

Metabolic Control . : 

a. Decrease in oxygen tension or the pH , ↑ Pco2 of portal venous blood ,typically lead to increase in hepatic arterial flow. b. Postprandial hyperosmolarity increases hepatic arterial & portal venous flow but not in the fasting state. c.The underlying metabolic and respiratory status (e.g., hypercapnia, alkalosis, arterial hypoxemia) also modulates the distribution of blood flow within the liver. Metabolic Control . 8

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Pressure-Flow Auto regulation a. Hepatic pressure auto-regulation keeps constant blood flow despite wide fluctuation in systemic BP. The mechanism involves myogenic responses of vascular smooth muscle to stretch. b.The hepatic artery exhibits pressure-flow auto regulation in metabolically active liver (postprandial) but not in the fasting state. c. Thus, hepatic flow autoregulation is not likely to be an important mechanism during anesthesia. 9

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c.Pressure-flow autoregulation is nonexistent in the portal circulation. d.Thus, decreases in systemic blood pressure—as often occur during anesthesia—typically lead to proportional decrease in portal venous flow. 10

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Extrinsic Regulation  Neural Control  Fibers of the vagus, phrenic, and splanchnic nerves (postganglionic sympathetic fibers from T6 to T11) enter the liver at the hilum. When sympathetic tone decreasessplanchnic reservoir volume increases. Sympathetic stimulation  translocates blood volume from the splanchnic reservoir to the central circulation. Vagal stimulation alters the tone of the presinusoidal sphincters , the net effect is a redistribution of intrahepatic blood flow without changing total hepatic blood flow. 11

Humoral control gastrin, glucagon, secretin, bile salts,angiotensin II, vasopressin, and catecholamines. cytokines, interleukins, and other inflammatory mediators have been implicated in the alteration of normal splanchnic and hepatic blood flow : 

12 Humoral control gastrin, glucagon, secretin, bile salts,angiotensin II, vasopressin, and catecholamines. cytokines, interleukins, and other inflammatory mediators have been implicated in the alteration of normal splanchnic and hepatic blood flow

Effect of Anesthetics on Hepatic Function. : 

Biochemical and Physiologic Functions of the Liver. 1, Intermediary Metabolism. synthesis & metabolism of protien,lipid,carbohydrate,bile & enterohepatic circulation. 2, Coagulation Coagulants and Procoagulants, Vitamin K Cofactor and γ-Carboxylation 3, Erythropoiesis and Erythrocytosis 4, Endocrine Physiology. 5, Immune and Inflammatory Responses. 6, Xenobiotic (Drug) Metabolism and Excretion. Effect of Anesthetics on Hepatic Function. 13

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Anesthesia & anaesthetic drugs affects the hepatic function by following mechanisms : 1.Alteration in the hepatic blood flow n HABR. 2.Metabolic function. 3.Drug metabolism. 4.Billiary function. 5.Liver Tests 14

1.Alteration of in hepatic blood flow n HABR. : 

Both regional n general anaesthesia reduces hepatic blood flow. All volatile anesthetics ↓ MAP n CO Reflex sympathetic stimulation  vasoconstriction of HA & PV ↓ THAB. Regional A  ↓MAP ↓ THAB. CPPV with high mean airway pressure ↓ venous return & CO ↓ THAB PEEP accentuates these effects. Spontaneous ventilation maintains hepatic blood flow. 15 1.Alteration of in hepatic blood flow n HABR.

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Hypoxemia decrease Hepatic blood flow through SYMP Activation. Hypercapnia ,hypocapnia,acidosis, alkalosis have variable effects on hepatic blood flow due to complex interaction. Surgical procedure near liver  reduce hepatic blood flow by 60%, due to symp activation, local reflexes, direct compression on vessels. 16

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2.Metabolic function. The effects of anaesthetics on hepatic intermediary metabolism ( carbohydrate, fat,protien ) is poorly understood. “ Endocrine stress response ”(↑ cortisol, glucagon & catecholamines) secondary to fasting n surgical trauma is observed. This Endocrine stress response may be partially blocked by regional & general anaesthesia,pharmacological blocked of sympathetic system. 17

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3.Drug metabolism. Anesthetics (eg.halothane )may directly inhibit the metabolism of several drugs ( phenitoin, warfarin, ketamine ). But it is probably because of decreased hepatic blood flow caused by various Anesthetic agents. 18

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4.Billiary function. Anaesthetic interaction with bile formation n storage have been not reported. However all opiods may cause spasm of sphincter of Oddi & increase billiary pressure. 19

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VOLATILE ANASTHETICS. halothane HALOTHANE IS COLOURELESS LIQUID WIDELY USED AS A INHALATIONAL AGENT. Halothane causes vasoconstriction, ↑ hepatic arterial resistance,& has a dramatic impact on HABF. Halothane also reduces hepatic oxygen delivery and hepatic venous oxygen saturation .These changes are related to ↓ MAP and ↓ cardiac output. 20

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Volatile anesthetic-induced alterations in hepatic blood flow are mediated by an auto regulatory mechanism the hepatic arterial buffer response (HABR) that maintains constant THBF. Halothane appears to disrupt this compensatory response, whereas sevoflurane and isoflurane maintain HABR. 21

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Sevoflurane suppresses hepatic arterial vasoconstriction and thus maintains HABF more effectively than halothane does. Sevoflurane is also consistently equivalent or superior to isoflurane in maintaining HABF, hepatic O2 delivery, and O2 delivery-to-consumption ratios. 23

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Impact of halothane, enflurane, isoflurane, and sevoflurane at 1.5 and 2.0 minimum alveolar concentration (MAC) on hepatic arterial oxygen delivery in chronically instrumented dogs. Halothane produced the greatest reduction in hepatic arterial oxygen delivery, whereas sevoflurane and isoflurane had insignificant effects on oxygen delivery at any MAC level. 24

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Of the halothane taken up during anesthesia, 20 to 46% is metabolized, compared with- Enflurane - 2.5 to 8.5%, Sevoflurane - 2 to 5%, Isoflurane -0.2 to 2%, Desflurane -0.02% . Each anesthetic, with the exception of sevoflurane, is oxidized via cytochrome P450 2E1 to yield highly reactive intermediates that bind covalently (acylation) to a variety of hepatocellular macromolecules . Halothane metabolism leads acid chloride,trifluracetic acid.tissue protein lysin. 25

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Halothane hepatitis Halothane hepatitis is immunologically mediated,as it induces both neoantigens & auto antigens. The incidence of fulminant hepatic necrosis terminating in death associated with halothane was found to be 1 per 35,000. Demographic factors ; ~ It’s a idiosyncratic reaction. ~ Mexican Americans are more susceptible ~Obese woman, ~ Age >50 yrs, ~ Familial predisposition . ~ Severe hepatic dysfunction, ~ Children are resistant. 26

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Important risk factor prior exposure to halothane & multiple exposure increases the likelihood of hepatitis. Previous exposure has also been reported as a factor in isoflurane-associated hepatitis. C/F ; Halothane CAUSES HEPATITIS WHICH IS A CENTRILOBULAR NECROSIS. It has to be differentiated from other viral hepatitis. Having latency of days, fever, anorexia, nausea, chills, myalgias, and rash, followed by the appearance of jaundice 3 to 6 days later. 27

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Laboratory findings ~ Elevated liver enzymes. ~ Peripheral eosinophilia, ~Circulating immune complexes, ~Organ nonspecific autoantibodies. Management ; *symptomatic & supportive. *early detection and treatment of complications, particularly ,metabolic acidosis (early), renal failure, cerebral edema, and infection. *coricosteroids ,if there is no improvement. * consideration of an orthotopic liver transplant for those patients in the poor prognosis group. 28

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ISOFLURANE. Isoflurane metabolism also yields highly reactive intermediates (TF-acetyl chloride; acyl ester) that bind covalently to hepatic proteins. The likelihood that isoflurane causes hepatitis via production of these intermediates appears to be extremely low, as just 0.2% of the isoflurane taken up into the body is actually metabolized. Only trace amounts of isoflurane-derived adducts are bound to hepatic proteins following isoflurane anesthesia 29

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It undergoes minimal biodegradation, preserves microvascular blood flow & oxygen delivery more than halothane or enflurane even during open laparotomy. 30

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DESFLURANE. which is similarly biotransformed to trifluoroacyl metabolites, appears even less likely than isoflurane to cause immune injury because only 0.02 to 0.2% of this agent is metabolized (1/1,000th that of halothane). Desflurane metabolites are usually undetectable in plasma, except after prolonged administration. 31

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Desflurane ↓hepatic blood flow in both experimental and clinical settings. Desflurane can markedly reduce oxygen delivery to the liver and small intestine without producing comparable reductions of hepatic oxygen uptake or hepatic and mesenteric metabolism. Therefore, desflurane anesthesia may decrease the oxygen reserve capacity of both the liver and the small intestine. 32

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SEVOFLURANE It is metabolized more extensively than is isoflurane or desflurane, slightly less than enflurane, and much less than halothane. The metabolism of sevoflurane (primarily via cytochrome P450 2E1) is rapid (1.5 to 2 times faster than enflurane), and produces detectable plasma concentrations of fluoride and hexafluoroisopropanol (HFIP) within minutes of initiating the anesthesia. 33

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The liver conjugates most of the HFIP with glucuronic acid, which is then excreted by the kidney. 34

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An important distinction between sevoflurane and the other volatile agents is that sevoflurane produces neither highly reactive metabolites nor fluoroacetylated liver proteins. There is no evidence that any sevoflurane metabolites cause severe hepatic injury. 35

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It suppresses hepatic arterial vasoconstriction and thus maintains HABF more effectively than halothane does. Sevoflurane is also consistently equivalent or superior to isoflurane in maintaining HABF, hepatic O2 delivery, and O2 delivery-to-consumption ratios. Sevoflurane anesthesia usually preserves blood flow and oxygen delivery to the liver, even in the presence of positive-pressure ventilation 36

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NITROUS OXIDE Nitrous oxide produces a mild increase in sympathetic nervous system tone. Consequently, one would expect mild vasoconstriction of the splanchnic vasculature, leading to a decrease in portal blood flow, and mild vasoconstriction of the hepatic arterial system. N2O is a known inhibitor of the enzyme methionine synthase, which could potentially produce toxic hepatic effects. 37

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Decrease in methionine synthase activity in the livers of animals and humans, and prolonged exposure will induce a functional vitamin B12 deficiency. There is no convincing evidence that nitrous oxide per se causes hepatotoxicity in the absence of a precarious oxygen supply–demand ratio in the liver. 38

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In summary, the influence of volatile anesthetics on hepatic blood flow and function is complex not just related to drug but also underlying hepatic dysfunction n surgical procedure . sevoflurane, desflurane, and isoflurane have been consistently shown to better preserve hepatic blood flow and function than halothane or enflurane. 39

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Intravenous Anesthetics. Less information is available regarding the impact of intravenous anesthetics on hepatic function . Etomidate and thiopental at larger doses (>750 mg) may cause hepatic dysfunction by ↓ hepatic blood flow, either from ↑ hepatic arterial vascular resistance or from reduced cardiac output and blood pressure. whereas ketamine has little impact on hepatic blood flow, even with large doses. 40

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propofol increases Blood Flow in both the hepatic arterial and portal venous circulation, suggesting a significant splanchnic vasodilator effect . Prolonged infusion of propofolhepatocellular injury, lactic acidosis,bradydysrhythmias & rhabdomyolysis. Based on limited clinical and experimental data, intravenous anesthetics have only a modest impact on hepatic blood flow and no meaningful adverse influence on postoperative liver function when arterial blood pressure is adequately maintained. 41

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Central Neuraxial Blockade The effect of spinal or epidural anesthesia on liver blood flow and hepatic function is not clearly an anesthetic drug-induced alteration. Presumably, hypotension-induced reductions in hepatic blood flow are secondary to decreased splanchnic blood flow and, thus, reduced PBF. 42

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OPIOIDS Opioids have little effect on hepatic function, provided they do not impair hepatic blood flow and oxygen supply. All opioids increase tone of the common bile duct and the sphincter of Oddi, as well as the frequency of phasic contractions, leading to increases in biliary tract pressure and biliary spasm. Fentanyl >morphine>pethidine> butorphanol> nalbuphine. 43

Effect of Hepatic Dysfunction and Hepatobiliary Disease on Anesthetic Drug Pharmacokinetics : 

Liver disease may have a significant impact on drug metabolism and pharmacokinetics as a result of – alterations in protein binding, reduced levels of serum albumin and other drug-binding proteins, altered volume of distribution because of ascites and increased total-body water compartments, reduced metabolism secondary to abnormal hepatocyte function. Effect of Hepatic Dysfunction and Hepatobiliary Disease on Anesthetic Drug Pharmacokinetics 44

Neuromuscular Blocking Drugs : 

The volume of distribution of muscle relaxants, may increase substantially for various reasons, including ↓ albumin an increase in γ-globulin or the presence of edema. These factors appear to account for the so-called “resistance” to such agents and explain ,why the initial dose requirements of these medications are increased in cirrhotic patients. However, subsequent dose requirements may be ↓, and drug effects prolonged, owing to ↓ in hepatic blood flow and impaired hepatic clearance, and possible concurrent renal dysfunction. Neuromuscular Blocking Drugs 45

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Vecuronium is a steroidal muscle relaxant It undergoes hepatic elimination by acetylation. Decreased clearance, a prolonged elimination half-life, and prolonged neuromuscular blockade in patients with cirrhosis . Rocuronium, another steroidal muscle relaxant with a faster onset of action than vecuronium, also undergoes hepatic metabolism and elimination. Hepatic dysfunction can increase the volume of distribution of rocuronium, thereby prolonging its elimination half-life and producing a longer clinical recovery profile and return of normal twitch tension. 46

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Atracurium & Cisatracurium; 82%to Bound albumin. undergoes clearance by organ-independent elimination 1) spontaneous non-enzymatic degradation (Hoffmann's elimination). 2) spontaneous hydrolysis by non-specific plasma esterases end product inactive laudonosine. Elimination half-lives and clinical durations of action are similar in cirrhotic & normal patients. Laudanosine, a metabolite of both atracurium and cisatracurium, is eliminated primarily by the liver; and although its concentration may increase in patients undergoing liver transplantation, clinically relevant neurotoxicity has not been reported. 47

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In summary, cirrhosis and other forms of advanced liver disease will predictably reduce the elimination of vecuronium, rocuronium, and mivacurium and prolong the duration of neuromuscular blockade, especially after repeated doses or the use of prolonged infusions. Atracurium and cisatracurium are not dependent on hepatic elimination and can be used without modification of dosing in patients with end-stage liver disease. 48

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Opioids. Morphine Morphine undergoes conjugation with glucoronic acid at hepatic & extra hepatic site (kidney). The significantly reduced metabolism of morphine in patients with advanced cirrhosis leads to a prolonged elimination half-life, markedly increased bioavailability of orally administered morphine, decreased plasma protein binding, and potentially exaggerated sedative and respiratory-depressant effects. The oral dose of the drug should be reduced because of increased bioavailability. 49

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Meperidine Meperidine undergoes extensive hepatic metabolism by demethylation. Similar changes like morphine occur with meperidine, for which there is a 50% reduction in clearance and a doubling of the half-life. In addition, clearance of normeperidine is reduced and patients with severe liver disease may experience neurotoxicity from accumulation of normeperidine. 50

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Fentanyl Fentanyl is a highly lipid-soluble synthetic opioid , With repeated administration or continuous infusions, accumulation may occur and lead to prolonged effects. Because fentanyl is almost completely metabolized in the liver, its elimination should be predictably prolonged in patients with advanced liver disease. However, fentanyl elimination is not appreciably altered in patients with cirrhosis 51

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Remifentanil Remifentanil is a synthetic opioid with an ester linkage that allows for rapid hydrolysis by blood and tissue esterases; such hydrolysis leads to high clearance, rapid elimination, and recovery that is almost independent of the dose or duration of infusions. Remifentanil elimination is indeed unaltered in patients with severe liver disease or in those undergoing liver transplantation.. 52

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Sedative/Hypnotic Drugs. Thiopental has a small hepatic extraction ratio, and therefore its metabolism and clearance should be adversely affected in patients with liver disease. However, the elimination half-life of thiopental is unchanged in cirrhotic patients, possibly because of a large volume of distribution. Etomidate clearance is unchanged in cirrhotic patients 53

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Methohexital and propofol also have an elimination kinetic profile in cirrhotic individuals that is similar to that in normal patients. However, mean clinical recovery times may be longer after discontinuation of propofol infusions in cirrhotic patients. 54

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Midazolam The reduced clearance of midazolam in patients with end-stage liver disease produces prolonged elimination half-lives. In conjunction with reduced protein binding and increased free fractions of midazolam, a prolonged duration of action and an enhanced sedative effect should be anticipated in patients with severe liver disease, especially after multiple doses or prolonged infusions. Similar changes have also been observed with diazepam. 55

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Patients with hepatic disease, either parenchymal or cholestatic, have peripheral vasodilatation,systemic shunting,and a reduced sensitivity to vasopressor drugs. While patients with advanced liver disease often require reduced doses of CNS depressants, they require increased doses of catecholamine or addition of a nonadrenergic vasoconstrictor. Patients with biliary obstruction would have an impaired hemodynamic response to blood loss. An impairment of the Ability to translocate blood from pulmonary and splanchnic blood reservoirs to the systemic Circulation would render patients highly susceptible to arterial hypotension from bleeding. 56

Risk Factors for Postoperative Hepatobiliary Complications- scoring system. : 

Cirrhosis as a Perioperative Risk Factor. A syndrome of end-stage liver disease pathologically characterized by severe fibrosis and nodular regeneration of the liver parenchyma. Causes ; Alcohol abuse(most common), chronic hepatitis, primary biliary cirrhosis, hemochromatosis, Wilson's disease, and idiopathic cirrhosis etc. 57 Risk Factors for Postoperative Hepatobiliary Complications- scoring system.

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Modified Child-Turcotte-Pugh Scoring System Parameters Modified Child-Turcotte-Pugh Score *   1 2 3 Albumin (g/dL) >3 2.8-3.5 <2.8 Prothrombin time   Seconds prolonged 4 4-6 >6 INR <1.7 1.7-2.3 > 2.3 Bilirubin (mg/dL) <2 2-3 >3 Ascites Absent Slight-moderate Tense Encephalopathy None Grade I-II GR III-IV 58

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Class A = 5-6 points, Class B = 7 to 9 points, and Class C = 10 to 15 points. For cholestatic diseases (e.g., primarily biliary cirrhosis), the bilirubin level is disproportionate to the impairment in hepatic function . assign 1 point for bilirubin level < 4 mg/dL, 2 points for 4 to 10 mg/dL, 3 points for > 10 mg/dL. 59

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Garrison and coworkers retrospectively evaluated outcomes in 100 patients with histologically proven cirrhosis who were undergoing surgery predominantly for biliary tract procedures ,gastro duodenal repair, colon and small bowel resection, and open liver biopsy. An overall operative mortality of 30% and an additional perioperative morbidity of 30% were noted, with sepsis-mediated multiorgan system failure being the major cause of death (87%). When stratified to CTP classes A, B, or C, mortality was 10%, 31%, and 76%, respectively. 60

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The Model for End-Stage Liver Disease, or MELD, is a scoring system for assessing the severity of chronic liver disease. It was initially developed to predict death within 3 months of surgery in patients who had undergone a transjugular intrahepatic portosystemic shunt (TIPS) procedure & FOR ALLOCATION OF LIVER TRANSPLANT. It uses the patient's values for serum bilirubin, serum creatinine, and the INR for prothrombin time to predict survival. MELD = 3.8 x log (e) (bilirubin mg/dL) + 11.2 x log (e) (INR) + 9.6 log (e) (creatinine mg/dL) Caveats with the score include: The maximum score given for MELD is 40. All values higher than 40 are given a score of 40 61

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If the patient has been dialyzed twice within the last 7 days, then the value for serum creatinine used should be 4.0. Any value less than one is given a value of 1 (i.e. if bilirubin is 0.8, a value of 1.0 is used) Interpretation In interpreting the MELD Score in hospitalized patients, the 3 month mortality is: 40 or more — 100% mortality 30–39 — 83% mortality 20–29 — 76% mortality 10–19 — 27% mortality <10 — 4% mortality. If age of patient is less than 12 yrs PELD Score 62

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Surgical Procedures That Increase the Risk of Postoperative Liver Failure : Actual surgical procedure  important risk factor for postoperative liver failure. Normal liver  adaptable to changes in perfusion pressure ,while diseased liver not. Abdominal surgery  reduces THBF. Surgical manipulation of the splanchnic bed may reduce both PBF and HABF. The effect of pneumoperitoneum on hepatic blood flow remains controversial. 63

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In addition to surgery on the biliary tract, stomach, and colon, hepatic resection for HCC is a known risk factor for the development of liver failure in patients with preoperative hepatic dysfunction. Perioperative hemorrhage is a common occurrence in cirrhotic patients undergoing resection for HCC because of contributing factors such as portal hypertension, coagulation abnormalities, and highly vascular adhesions in those with previous abdominal surgery. 64

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SUMMARY : Cirrhosis is still considered a major risk factor for patients undergoing nonhepatic surgery, with elective surgery considered contraindicated in CTP class C patients. It is prudent to avoid elective surgery in cirrhotic patients with a prolonged INR, hypoalbuminemia, and evidence of preoperative infection or encephalopathy. Preoperative decompression of portal hypertension by TIPS may also improve postoperative outcomes in certain patients. When diagnosis of cirrhosis is made at the time of Sx ,it is wise to avoid elective abdominal procedures. 65

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