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Anesthesia and the liverBydr. marwa a.mahrousassisstant lecturer anesthesia and icu sohag university

Sources of this lecture:HEPATIC ANATOMY,PHYSIOLOGY & ANESTHETIC EFFECTS, Dr. Mohd Saif Khan MD ,LHMC, New DelhiRISK OF SURGERY IN THE PATIENT WITH LIVER DISEASE, Ajay Jain,Gastroenterology Fellow ,January 16, 2002.ANAESTHESIA AND LIVER DISEASES, DR.D.KIRUBAKARAN,2011.08.08Dr. C.K. Pandey,new delhi, anesthetic consideration and perioperative risks in patient with liver disease.

Objectives -anatomy, physiology and function of the liver-effect of anesthesia on liver function-effect of liver function on anesthetic drugs-anesthesia for a patient with liver disease: hepatitis:acute,chronic cirrhosis

HEPATIC ANATOMYGROSS ANATOMYMICROSCOPIC ANATOMYHEPATIC BLOOD FLOWHEPATIC BLOOD FLOW REGULATIONINTRINSIC FACTORSEXTRINSIC FACTORSEFFECTS OF ANESTHESIA ON HBFHEPATIC FUNCTIONSANESTHETIC AGENTS & HEPATIC FUNCTIONS

This seminar includes 4

GROSS ANATOMYLargest internal organlargest gland Wt. :median weight of 1.8 kg in men and 1.4 kg in women. It accounts for about 2% of the total mass of healthy adults and 5% of neonates.Location : Rt. HypochondriumIn the right midaxillary line, the liver spans from the 7th to the 11th ribs.It is covered by peritoneum (Glisson's capsule), except for the gallbladder bed, the inferior vena cava (IVC), the bare area, and the porta hepatis.

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LOBES vs SEGMENTS OF THE LIVERCustomary division -into 4 lobes-the right, left, caudate, and quadrate lobes is derived from the topographic anatomy, with the falciform ligament separating the right and left lobes.

This anatomic description does not correspond to the branches of the liver's vascular supply and therefore is of limited clinical and physiologic significance. The segmental division of the liver was devised by Couinaud, based on third-generation branches of the portal vein to partition the liver into eight physiologically independent segments.This anatomic arrangement facilitates limited segmental resection of the liver with relatively bloodless surgical dissection along the planes between segments, and thereby prevents major disruption of hepatobiliary function. segment I (the caudate lobe) gets its blood supply from both left and right main portal veins; and, it drains directly into the inferior vena cava (IVC).Clinical studies have shown lower rates of perioperative morbidity and mortality when liver surgery (resection of tumors, repair of traumatic injuries) is guided by the principles of physiologic anatomy.

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The liver is separated into eight anatomic segments, each with an independent nutrient blood supply and venous and biliary drainage. Appreciation of this segmental anatomy is the basis of anatomic resection of the liver.

Functional/segmental division- Divided into 8 segments each receiving a portal pedicle.Couinaud system of divisionBased on distribution of blood flow via portal pedicles and location of hepatic vein.

Biliary system BILE CANALICULIRT. & LT. HEPATIC DUCTCOMMON BILE DUCTCOMMON HEPATIC DUCTCYSTIC DUCTDUODENUM

MAIN PANCREATIC DUCT

Biliary system for excretion of bile from the liver into the intestine. Some of the bile is stored in the gall bladder. The common bile duct enters the duodenum at the duodenal papilla. Its orifice is surrounded by the sphincter of Oddi, and it usually unites with the main pancreatic duct just before entering the duodenum. 8

GALL BLADDERConcetration and storage of bileLocation : inferior surface of liver7-10 cm longCapacity : 30-50 ml Blood supply: cystic arteryAnesthetic interactions with bile formation and storage have not been reported. All opioids can potentially cause spasm of the sphincter of Oddi and increase biliary pressure .(fenta causes max spasm).

liver bile is 97% water, whereas the average water content of gallbladder bile is 89%. The production of bile is increased by stimulation of the vagus nerves and by the hormonesecretin, which increases the water and HCO3 content of bile. Substances that increase the secretion of bile are known as choleretics. Bile acids themselves are among the most important physiologic choleretics.Anesthetic interactions with bile formation and storage have not been reported. However, all opioids can potentially cause spasm of the sphincter of Oddi and increase biliary pressure (fentanyl > morphine > meperidine > butorphanol > nalbuphine). 9

Venous drainage of liver

If thrombosis of the major hepatic veins occurs (Budd-Chiari syndrome), the caudate veins become the key to drainage of hepatic blood into the IVC. The caudate lobe is usually drained by its own set of veins.

In portal hypertension portosystemic shunts dilated.

CENTRAL VEINSINTER LOBULAR & SUBLOBULAR VEINS3 HEPATIC VEINSIVC

HEPATIC SINUSOIDS

An important function of the liver is to serve as a filter between the blood coming from the gastrointestinal tract and the blood in the rest of the body. Blood from the intestines and other viscera reach the liver via the portal vein. This blood percolates in sinusoids between plates of hepatic cells and eventually drains into the hepatic veins, which enter the inferior vena cava. During its passage through the hepatic plates, it is extensively modified chemically. Bile is formed on the other side at each plate. The bile passes to the intestine via the hepatic duct The caudate lobe is usually drained by its own set of veins.10

LYMPHATIC DRAINAGE

SUPERFICIALDEEPCAVALHEPATICCOELIACPARACARDIALNODES AROUND IVC &HEPATIC NODES

The liver is supplied by sympathetic nerve fibers (T6T11), parasympathetic fibers (right and left vagus), and fibers from the right phrenic nerve. Portal hypertension and increased hepatic venous pressure can markedly increase hepatic lymph flow and lead to transudation through the hepatic capsule into the peritoneal cavity, producing ascites.The liver is predominantly innervated by two plexuses that enter at the hilum and supply both sympathetic and parasympathetic nerve fibers. The anterior plexus surrounds the hepatic artery and is composed of postganglionic sympathetic fibers from the celiac ganglia and parasympathetic fibers from the anterior vagus nerve. The posterior plexus surrounds the portal vein and bile duct, and is formed from branches of the right celiac ganglia and posterior vagus. Stimulation of the sympathetic fibers alters hemodynamics and metabolism of the liver. Hepatic vascular resistance increases and blood volume decreases, whereas glycogenolysis and gluconeogenesis increase, producing an increase in the blood glucose concentration. Parasympathetic stimulation increases glucose uptake and glycogen synthesis.

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SYMPATHETIC(T6-T11)From celiac gangliaPARASYMPATHETIC(VAGUS)HEPATIC PLEXUS

Stimulation causes Hepatic vascular resistanceTHBF & blood volumeGlycogenolysis Glucose output

Nerve supply of liverVAGAL STIMULATION DUE TO SURGERYAROUND GALL BLADDER BED. BRADYCARDIA

Stimulation of the sympathetic fibers alters hemodynamics and metabolism of the liver. Hepatic vascular resistance increases and blood volume decreases, whereas glycogenolysis and gluconeogenesis increase, producing an increase in the blood glucose concentration. Parasympathetic stimulation increases glucose uptake and glycogen synthesis.

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MICROSCOPIC ANATOMYKIERMANS LOBULEFunctional unit of liver50,000100,000 in number.Each lobule is composed of plates of hepatocytes arranged cylindrically around a centrilobular vein.

RAPPAPORT ACINUSParenchymal mass between 2 centrilobular veinsCentre /Axis is formed by PORTAL TRIAD

Portal Axis consists of a terminal portal venule, a hepatic arteriole and a bile ductule

In contrast to the direction of blood flow, bile flows in the opposite direction from perivenular hepatocytes to the portal tract bile ducts. Centripetal flow of blood in sinusoids to central vein and centrifugal flow of bile in bile canaliculi to bile ducts.The organization of the hepatic parenchyma has been conceptualized in two contrasting models: Kierman's classic lobule and Rappaport's acinus.

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3 zones of hepatocytes based on Concentration gradients of oxygen and solutes occur along the sinusoidal spaces.

IIIIIICentral veinPortal triadZONESZONALITY(zonal relationship ) IN LIVER LOBULE

Liver lobule

Liver Acinus functional microvascular unit

ZONE I (PERIPORTAL)O2 TENSION=250mmHgLEAST SUSCEPTIBLE TO ISCHEMIAZone 1- rich in Oxygen, mitochondria Oxidative metabolism, synthesis of glycogen Zone 2- transition

ZONE I & II BOTH Chief producer of NH3Contain enzymes for urea cycle No. Of mitochondria

ZONALITY(zonal relatioship ) IN LIVER LOBULE

IIIIIICentral veinPortal triadZONES

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17Hepatic MicrocirculationLiver Acinus functional microvascular unitZone 1- rich in Oxygen, mitochondriaOxidative metabolism, synthesis of glycogenZone 2- transitionZone 3- lowest in Oxygen, anaerobic metabolism, Cytochrome P-450 Biotransformation of drugs, chemicals, and toxinsMost sensitive to damage due to ischemia, hypoxia, congestion

ZONE IIILast to receive blood hence O2 TENSION= 70mmHg, lowest in OxygenMost susceptible to ischemiaMost sensitive to damage due to ischemia, hypoxia, congestionAnaerobic metabolismDetoxification & Biotransformation reactions Cytochrome P-450

Hence with hypoxic insult to liver Biotransformation of drugs is Amongst the first to be affected.ZONALITY(zonal relationship ) IN LIVER LOBULE

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.Centrilobular necrosis is the classic acetaminophen-induced injury; the probable explanation is that CYP2Ethe CYP isoform involved in acetaminophen metabolismis localized in zone 3.18

Metabolic diversity within zones Zone 1(periportal) Zone 3(pericentral) Rich in oxygen and the nutrientsRelatively poor in O2 and nutrients Less prone to hypoxia and drug toxicityMore prone for hypoxic & drug induced damage Oxidative/phaseII reaction Anaerobic/phaseI reaction Glycogen snthesis as well as gluconeogenesis Glycolysis Bile salt formation Lipolysis

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HEPATIC ULTRASTRUCTURE

HEPATOCYTES are arranged in plates with intervening sinusoids.

PITT CELLS : highly mobile lymphocytes

KUPFFER CELLS : macrophages attached to endothelium.

ITO CELLS : contain fat, store vit. A.

The liver cell plates are formed by cords of hepatocytes extending as one-cell-thick plates, 12 to 25 hepatocytes in length, between two vascular structures, the portal tract and the terminal hepatic venule.

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SPACE OF DISSE : Around sinusoids. Microvilli of hepatocytes are exposed to this space.

SINUSOIDS : specialized capillary system having fenestrated endothelium.

ENDOTHELIAL CELLS : fenestrated and highly permeable Allow exchange of molecules b/w hepatocytes and sinusoidal blood.

HEPATIC ULTRASTRUCTURE

HEPATIC BLOOD FLOW

Vascular supply of liver

20-30% of the cardiac output,Average blood flow between 100 and 130 mL/minute per 100 g.

Features H.A P.V Bl supply 25-30%70-75% 02 supply 45-50%50-55% Spo2 98%60-75% Mean BP 40-70 5-10

THBF 25 to 30% by hepatic artery and 70 to 75% by portal vein.

Hepatic oxygen consumption -45 to 50% by hepatic artery and 50 to 55% by the portal vein

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HEPATIC BLOOD FLOW REGULATIONINTRINSIC FACTORS(regional microvascular) EXTRINSIC FACTORS(neural and hormonal)HEPATIC ARTERIAL BUFFER RESPONSE

Metabolic controlPressure flow autoregulation

Neural controlHumoral control

Hepatic arterial flowappears dependent on metabolic demand postprandially (autoregulation), whereas flow through the portal vein is dependent on blood flow to the gastrointestinal tract and the spleen.25

Intrinsic regulationHepatic arterial buffer response Decrease in portal biood flow and oxygen tension will increase the hepatic arterial blood flow thru increased periarteriolar adenosine whereas increase in portal blood flow decrease the HABF thru decrease in periarteriolar adenosine. In portal HT Liver depend upon hepatic arterial blood flow as HABR reaches its upper limit.(oxygen supply and demand should be carefully maintained)

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Intrinsic RegulationPressure FLOW AUTOREGULATION Exist even when the SBP reaches 80mmhg. Myogenic reflex High TM pressure decreases flow Low TM pressure - increases flow Autoregulation Doesnt exist in portal circulation.FOOD RELATED (metabolic control) Postprandial hyperosmolarity increases both portal & HBF.

Hepatic arterial system undergoes flow autoregulation best when the liver is very active metabolically(postprandial) but not during fasting state . Hence flow autoregulation is not likely to be an important mechanism during most anaesthetics, given that they are performed in fasted patients.

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Extrinsic regulationCirculatory regulation neural

Blood flow through portal vein is indirectly regulated by vasoconstriction and vasodilatation of splanchnic arterial bed whereas hepatic arterial flow is directly regulated thro sympathetic system.

Hepatic artery both alpha and beta receptors. Portal vein - contains only alpha receptors.

Hormonal regulation glucagon - increases hepatic arterial blood flow. angiotensin - decreases both portal and hepatic blood flow. vasopressin - decreases both portal and hepatic blood flow.

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Extrinsic regulation Catecholamines

Portal vein - vasoconstriction. Hepatic artery - vasoconstriction in low dose. vasodilatation in high dose.

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Decreased hepatic blood flowUpright postureHypocarbiaHypoxiaIPPV/PEEPSepsisHaemorrhageMesentric tractionIncreased IA pressureAlpha agonistBeta blockersVasopressinOctreotideVolatile anaestheticsIntravenous induction agentsRegional anaesthesia

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Increased hepatic blood flowSupine posture

Postprandial state

Hypercarbia

Acidosis

Acute hepatitis Beta agonist

Phenobarbitone

Glucagon

Dopamine

Dopeximine

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EXTRINSIC FACTORS HEPATIC BLOOD FLOWFeeding (hyperosmolarity)Glucagon agonistsRecumbent positionHepatocellular enzyme inductionAcute hepatitis?hypercapnia

HEPATIC BLOOD FLOWAnesthetic agentsSurgical trauma agonists/ blockersIPPV/PEEPVasopressinHepatic cirrhosis?hypocapnia

Glucagon induces a graded, long-lasting dilation of hepatic arterioles; it also antagonizes arterial constrictor responses to a wide range of physiologic stimuli, including stress-induced sympathoadrenal outflow.The hepatic artery has 1-adrenergic vasoconstricting receptors as well as 2-adrenergic, dopaminergic (D1), and cholinergic vasodilator receptors. The portal vein has only 1-adrenergic and dopaminergic (D1) receptors. Sympathetic activation results in vasoconstriction of the hepatic artery and mesenteric vessels, decreasing hepatic blood flow. -Adrenergic stimulation vasodilates the hepatic artery; -blockers reduce blood flow and, therefore, decrease portal pressure. Vasopressin also intensely constricts splanchnic vessels, markedly reducing flow into the portal vein. This action accounts for the efficacy of high-dose vasopressin (0.2 to 0.4 U/minute intravenously) to alleviate portal hypertension and decrease bleeding from esophageal varices.

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EFFECTS OF ANESTHESIA ON HBFINHALATIONAL AGENTSI.V. ANESTHETIC AGENTSVENTILATIONCENTRAL NEURAXIAL BLOCKADEHYPOXIAPaCO2TYPE OF SURGERY

INHALATIONAL AGENTS & HBFHALOTHANE- max. vasoconstriction in hepatic arteriolar vascular bed, reduces hepatic O2 delivery & hepatic venous O2 saturation.Disrupts HABR.ENFURANE Same effect as halothane but with lesser intensity.ISOFLURANE/SEVOFLURANE Maintains HABRSevoflurane is also consistently equivalent or superior to isoflurane in maintaining HABF, hepatic O2 delivery, and O2 delivery-to-consumption ratios.

Nitrous oxide on HBFNitrous oxide containing anaesthetics does not cause liver injury in the absence of impaired hepatic oxygenation.

Nitrous oxide may exacerbate hepatic damage in the presence of impaired hepatic oxygenation through sympathetic stimulant action and methionine synthase inhibition.

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EFFECTS OF ANESTHESIA ON HBFI.V. ANESTHETIC AGENTS- PV blood flow Total HBF is unchanged.Propofol is the best IV induction agent as it does not disrupt HABR.

VENTILATION-Spontaneous- no changeIPPV- HBF ( C.O.)Positive end-expiratory pressure (PEEP) further accentuates these effects.

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.

Controlled positive pressure ventilation with high mean airway pressures reduces venous return to the heart and decreases cardiac output; both mechanisms can compromise hepatic blood flow. The former increases hepatic venous pressure, whereas the latter can reduce blood pressure and increase sympathetic tone. Positive end-expiratory pressure (PEEP) further accentuates these effects. Spontaneous ventilation therefore may bemore advantageous in maintaining hepatic blood flow. Hypoxemia decreases hepatic blood flow via sympathetic activation. 36

EFFECTS OF ANESTHESIA ON HBFCentral neuraxial blockade

Spinal block to T5 level 23% HBFHYPOXIAVasoconstriction in splanchnic & hepatic vasculature HBFEffect of hypoxia depends on duration, degree & anesthetic used.

MAP HBF PV BLOOD FLOW

-Adrenergic blockers, 1-adrenergic agonists, H2-receptor blockers, and vasopressin reduce hepatic blood flow. Low-dose dopamine infusions may increase liver blood flow.

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EFFECTS OF ANESTHESIA ON HBFPaCO2

HYPOCAPNIAHYPERCAPNIAVASOCONSTRICTION HBFVASODIALATIONSYMPATHETIC STIMULATION HBFHBF

EFFECT OF SURGERYSurgical procedures near the liver can reduce hepatic blood flow up to 60%. Probable mechanisms: sympathetic activation, local reflexes, and direct compression of vessels in the portal and hepatic circulations.

Surgical procedures near the liver can reduce hepatic blood flow up to 60%. Although the mechanisms are not clear, they most likely involve sympathetic activation, local reflexes, and direct compression of vessels in the portal and hepatic circulations.

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HEPATIC FUNCTIONS

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HEPATIC FUNCTIONSMETABOLIC EXCRETORY SYNTHETIC STORAGE OF BLOODReservoir functionIMMUNITY DETOXIFICATION BILIRUBIN METABOLISMENDOCRINE BLOOD COAGULATION

Normal hepatic blood volume is about 450 mL (almost 10% of total blood volume). A decrease in hepatic venous pressure, as occurs during hemorrhage, shifts blood from hepatic veins and sinusoids into the central venous circulation and augments circulating blood volume as much as 300 mL.40

Functions of liver A. Albumin synthesis B. Bilirubin secretion C. Coagulation factor synthesis D. Drug metabolism E. Excretion F. Fat metabolism G. Glucose & Glycogen metabolism H. Hormone metabolism I . Immunological function

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METABOLIC FUNCTIONSCarbohydrate metabolism-glucose buffer function

Protein metabolismdeamination urea cycleinterconversions between nonessential amino acids

Lipid metabolism oxidation of FAAcetyl CoAketone bodiesFFA esterified to form TAG.lipoprotein synthesisphospholipids & cholesterol synthesis

Glycogenesis Gloconeogenesis Glycogenolysis

EUGLYCEMIASURGICAL STRESS

NH3 FORMATION

glucose buffer function The liver performs a critical role in protein metabolism. Without this function, death usually occurs within several days. The steps involved include (1) deamination of amino acids, (2) formation of urea (to eliminate the ammonia produced from deamination), (3) interconversions between nonessential amino acids, and (4) formation of plasma proteins.The ammonia formed from deamination (as well as that produced by colonic bacteria and absorbed through the gut) is highly toxic to tissues. Through a series of enzymatic steps, the liver combines two molecules of ammonia with CO2 to form urea. The urea thus formed readily diffuses out of the liver and can then be excreted by the kidneys.

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SYNTHETIC FUNCTIONSPLASMA PROTEINS-Albumin (10-15g/day)Globulins except Ig.CLOTTING FACTORS- all coagulation factors except factor III,IV & VIII.ANTITHROMBIN III, PROTEIN C & SENZYMES-ALP,SGOT,SGPTPSEUDOCHOLINESTERASECHOLESTEROL, LIPOPROTEINS ,PHOSPHOLIPIDSACUTE PHASE REACTANTS

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BILE SYNTHESIS

BILE EXCRETION- 600-1200 ml/dayCHOLESTEROLBILE ACIDSBILE SALTSACTIVATION OF LIPASEEMULSIFICATION OF FAT

Bile is made up of the bile acids, bile pigments, and other substances dissolved in an alkaline electrolyte solution that resembles pancreatic juice.Phosphatidylcholine that enters the bile forms mixed micelles with the bile acids and cholesterol. The ratio of bile acids:phosphatidylcholine:cholesterol in canalicular bile is approximately 10:3:1. Deviations from this ratio may cause cholesterol to precipitate, leading to one type of gallstones.Several mechanisms are responsible for bile formation: (1) osmotic filtration primarily due to secretion of bile salts into canaliculi (bile salt-dependent fraction), (2) Na+K+-adenosine triphosphatasemediated ion transport (bile salt-independent fraction), and (3) secretin-mediated sodium and bicarbonate transport by ductules.44

BILIRUBINBILIVERDINBILIRUBIN GLUCURONIDE

EXCRETEDIN BILE

BILIRUBIN METABOLISM

Senescent RBCsHbHeme Non erythrocytic hemoproteins

75 %25 %Heme oxygenaseBiliverdin reductaseUDP Glucoronyl tarnsferase

DETOXIFICATIONLIPOPHYLIC XENOBIOTICSHYDROPHYLICMETABOLITESDETOXIFICATIONPHASE I REACTIONSPHASE II REACTIONSOxidation, Reduction, Hydrolysis N-AcetylationMediated by Cyt. P450Conjugation ReactionAddition of Glucuronic acid,Glycine Sulphate,Methyl gp.

INHALATIONAL AGENTS (HALOTHANE ESPECIALLY) COMPETITIVELY INHIBIT CYT P450 & PHASE I REACTION Ethanol, barbiturates, ketamine, and perhaps benzodiazepines (eg, diazepam) are capable of enzyme induction,

Phase 1 reactions are catalyzed by enzymes that introduce or expose a polar functional group such as a hydroxyl or amino moiety in a drug by oxidation and hydrolytic reactions, respectively, whereas phase 2 reactions often lead to enzymatic conjugation of these polar functional groups to very polar molecules. The net effect of these reactions is the formation of molecules that are more easily excreted into urine through the kidneys or into the gastrointestinal tract by biliary excretion. N-Acetylation is the exception because it leads to the formation of less water-soluble metabolites.Phase I reactions modify reactive chemical groups through mixed-function oxidases or the cytochrome P-450 enzyme systems, resulting in oxidation, reduction, deamination, sulfoxidation, dealkylation, or methylation. Barbiturates and benzodiazepines are inactivated by phase I reactions.Some enzyme systems, such as those of cytochrome P-450, can be induced by a few drugs. Ethanol, barbiturates, ketamine, and perhaps benzodiazepines (eg, diazepam) are capable of enzyme induction, increasing production of the enzymes that metabolize those drugs. This can result in increased tolerance to the drugs' effects. Moreover, enzyme induction often promotes tolerance to other drugs that are metabolized by the same enzymes (cross-tolerance). Conversely, some agents, such as cimetidine and chloramphenicol, can prolong the effects of other drugs by inhibiting these enzymes.Phase 3 Elimination Phase 3 reactions involve specific molecular transportersknown as ATP-binding cassette (ABC) transport proteinsthat facilitate the excretion of xenobiotics and endogenous compounds. These proteins use ATP hydrolysis to drive molecular transport. Major ABC transport proteins include cystic fibrosis transmembrane conductance regulator (CFTR), canalicular copper transporters, and multidrug resistance protein (MDR). MDR-1 (formerly called P-glycoprotein) resides on the canalicular surfaces of hepatocytes and enables biliary excretion of cationic compounds, including anticancer drugs.dysfunction of ABC transport proteins can disrupt the flow of bile, impair excretion of xenobiotics and endogenous compounds, and induce cholestatic liver injury. 46

Drug metabolismPhase I reaction

Carried out by cyto P450 enzyme system.

Zone 3 rich in cytochrome enzyme system.

Affected early by ageing and liver disease.

Most drug hepatotoxicity is mediated by the phase I toxic metabolite.

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Drug metabolismPhase II reaction conjugation reaction (glucuronic acid &sulfate).

Zone 1 rich in enzymes involved in conjugation.

Affected least by ageing and liver disease.

Products of phase 2 reaction are usually less toxic when compared to phase I reaction.

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DETOXIFICATIONPhase III reactionsinvolve specific molecular transportersknown as ATP-binding cassette (ABC) transport proteins.facilitate the excretion of xenobiotics and endogenous compounds. These proteins use ATP hydrolysis to drive molecular transport. Examples: cystic fibrosis transmembrane conductance regulator (CFTR), canalicular copper transporters, and multidrug resistance protein (MDR). MDR-1 (formerly called P-glycoprotein) resides on the canalicular surfaces of hepatocytes and enables biliary excretion of cationic compounds, including anticancer drugs.Dysfunction of ABC transport proteins can disrupt the flow of bile, impair excretion of xenobiotics and endogenous compounds, and induce cholestatic liver injury.

Phase 1 reactions (e.g., oxidations, reductions, hydrolysis) convert drugs to more polar compounds by inserting polar groups (e.g., OH, NH2, SH) or removing nonpolar groups.Phase 2 reactions conjugate xenobiotics (or their metabolites) with endogenous hydrophilic molecules such as glucuronic acid, acetate, sulfates, amino acids, and glutathione.Hepatic cirrhosis can down regulate cyp receptors leading to decreased metabolism of drugs.49

HEPATIC DRUG CLEARANCEGOVERNED BY-Rate of HBF.Plasma protein binding of drugHepatic intrinsic clearance.CLEARANCE :Volume of blood from which the drug is completely removed per unit TIME .CLEARANCE = HBF X EXTRACTION RATIO (Cl) (Q) (E)

The metabolism of a few drugsincluding lidocaine, morphine, verapamil, labetalol, and propranololis highly dependent on hepatic blood flow. Thesedrugs have very high rates of hepatic extractionfrom the circulation. As a result, a decrease in theirmetabolic clearance usually reflects decreased hepatic blood flow rather than hepatocellular dysfunction.

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Extraction ratioExtraction ratio is the proportion of the drug that is extracted in single passage through the liver.

ER = intrinsic clearance/ HBF

High extraction ratio ( 0.7 ) It is affected by the hepatic blood flow but not by factors that increase free fraction of drug.

Dose has to be reduced by as much as 50% but not the frequency of dosing.

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Extraction ratioLow extraction ratio

It is affected by intrinsic metabolic capacity But it is flow independent.i.e increase in flow doesnt increase extraction. Affected by factors that increase free fraction of the drug. Reduction in protein binding of highly protein bound drug causes almost doubling of free fraction but with poorly bound drug it doesnt have much effect. For low extraction drugs ,interval between the doses should be increased but the drug dosage should not be altered.

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ER provides a measure of the relative efficiency with which the liver extracts or eliminates a given drug.Amount of drug removed from blood during a single liver transit, expressed as a fraction of 1.CLEARANCE = HBF X EXTRACTION RATIO (Cl) (Q) (E)

HIGH EXTRACTION RATIOLOW EXTRACTION RATIOPropofolThiopentoneFentanyl, Morphine, MeperidineDiazepamLignocaineDigitoxinVerapamilPhenytoinLabetalolpancuroniumPropanolol

Clearance of drugs with high hepatic extraction ratio is more markedly affected by changes in HBF.

The metabolism of a few drugsincluding lidocaine, morphine, verapamil, labetalol, and propranololis highly dependent on hepatic blood flow. Thesedrugs have very high rates of hepatic extractionfrom the circulation. As a result, a decrease in theirmetabolic clearance usually reflects decreased hepatic blood flow rather than hepatocellular dysfunction.

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Ammonia Metabolism & Excretion

Ammonia is toxic to the central nervous system (CNS), and freely permeable across the bloodbrain barrierHEPATIC ENCEPHALOPATHY

Ammonia Metabolism & ExcretionThe liver is critical for ammonia handling in the body. Ammonia levels must be carefully controlled because it is toxic to the central nervous system (CNS), and freely permeable across the bloodbrain barrier. The liver is the only organ in which the complete urea cycle (also known as the Krebs-Henseleit cycle) is expressed (Figure 296). This converts circulating ammonia to urea, which can then be excreted in the urine (Figure 297).

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Liver function testsQuantitative - assess hepatic blood flow and the metabolic capacity.

Qualitative - assess hepatocellular necrosis. assess cholestasis. assess synthetic function. assess excretory function.

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Quantitative liver testHepatic blood flow or perfusionBromosulphothalein clearanceIndocyanine green clearanceRose bengal clearance testHepatic drug metabolising capacityGalactose elimination capacityAminopyrine breath testAntipyrine clearanceMonoethylglycinexylidide(MEGX) clearanceCaffeine clearance more expensive & time consuming

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Aminotransferace(ALT &AST) Alanine transaminase Aspartate transaminase Relatively liver specific Non specific CytosolCytosol and mitochondria Zone 1>3 Zone 3>1N.value O 45 IU/L N.Value 0 35IU/L Half life is 18hrs Half life is 36hrs

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Examples for raised ALT &AST Minor < 100 IU Chronic hepatitis B/ C NASH Fatty liver

Moderate 100-300IU Alcoholic hepatitis Autoimmune hepatitis Acute viral hepatitis Exacerbation of chronic viral hepatitis plus all the above condition

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Marked > 300 IU Drugs and toxins Acute viral hepatitis Ischaemic hepatitis Acute exacerbation of chronic hepatitis Extrahepatic cholestasis with cholangitis.

Eventhough it is a marker of hepatocellular necrosis, the degree of elevation does not correlate with the extent of necrosis.(no prognostic value). Examples for raised ALT &AST

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Aminotransferace(ALT &AST)AST/ALT ratio may be of value in differential diagnosis. >4 (wilsons hepatitis) 2-4 (alcoholic liver disease) 3fold normal value but the level remain elevated for 7-10days even after the obstruction resolves as the half life of ALP is 7days.

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Alkaline phosphataseValue < 3 fold elevation from normal value can be seen in normal people. Age> 60yrs upto 1.5 times increase Children - upto 2 times increase Pregnancy - upto 3 times increase B.G O & B - upto 3 times increase after a fatty meal

Only recomended use of GGT & 5-nucleotidase (most specific) is to exclude or to substantiate, liver is the source of raise ALP if the electrophoretic fractionation of ALP is not available.

Elevated ALP along with 5-nucleotidase is specific for the hepatobiliary diseases and also helps to R/O physiological ALP elevation.

Disproportinate elevation of ALP and bilirubin suggest the presence of infiltrative liver disease ( tumour, sarcaidosis,tuberculosis etc).

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Prothrombin timeNormal prothrombin time 11-14secs.PT >3-4s over control value is significant.Increasing PT is a ominuos sign in patient with acute hepatocellular disease (impending hepatic failure).Prothrombin time in contrast to s.albumin is a useful prognostic indicator in acute hepatocellular disease. ( as half life of CF is short IC to albumin) CLOTTING FACTORS- Rapid turn over(factor VII has shortest half life : 2-6 hr) Hence, best measure of acute hepatic dysfunction.Prothrombin time is the best testThe PT, which is normally 1114 s, measures the activity of fibrinogen, prothrombin, and factors V, VII, and X.

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Prothrombin timeMild moderate hepatic disease may not be detected by PT as only 30% of CF is needed for maintaining haemostasis.

Cholestatic jaundice -correction of PT by atleast 30%within 24 hr of vit k administration suggest hepatic synthetic function is intact ( prolonged PT due to vit k deficiency alone).

Prolonged PT >5sec above control not corrected by vitamin k administration is a poor prognostic sign ( in both acute and chronic liver disease).

INR is a better indicator than PT because it is a standardized value and is not subjected to lab variability as PT.

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Albumin Normal value 3.5 to 5.5gm/dl.

Blood level depends upon rate of synthesis(10-15gm/day),rate of degradation and plasma volume.

Half life of serum albumin is about 21 days Slow turn over ( half life : 18-20 days)

Not a good indicator of acute hepatic dysfunction because of slow turnover ( long half life with 4% degredation per day).

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Albumin In patients with hepatitis, albumin< 3gm/dl should raise the possibility of chronic liver disease.Decreasing albumin level in patient with chronic liver disease indicates worsening of liver function in the absence of other causes of hypoalbuminemia.As long as albumin level is more than 2.5gm per dl, free or unbound fraction of the drug wont be altered.Hypoalbuminemia is more common in chronic liver disorders such as cirrhosis and usually reflects severe liver damage

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Bilirubin Normal total bilirubin value is < 1mg/dl.Out of these, upto 0.3mg is conjugated bilirubin.

Unconjucated bilirubin is toxic for neuronal cell whereas the conjucated bilirubin is responsible for renal dysfunction in patient with obstructive jaundice. Bilirubin value rarely exceeds 6mg/dl in Haemolytic anaemia.

Intrahepatic cholestasis to cause rise in bilirubin, drainage of bile in >75% parenchyma should be blocked.

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Bilirubin In choledocholithisis caused by CBD stone, the bilirubin value rarely exceeds 10mg/dl.Sepsis or renal failure should be excluded if the bn exceeds 30mg/dl in patient with CBD stone.

In cholestatic jaundice due to malignancy, the bilirubin value is >10mg but but less than 30mg/dl.

Common bile duct obstruction if persist for more than 30 days will result inliver damage and can lead to the development of cirrhosis.

Serum bilirubin will take atleast 1-2 weeks to return to normal following the relief of obstruction ( half life of delta bn is 2weeks).

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Impaired liver function Direct effectsHypoglycemia, Lactic acidosis , Hyper metabolism, Azotemia and Impaired urea synthesis. Jaundice appears when serum bilirubin exceeds 35 mol/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

Indirect effects Cardiovascular changesVasodilatation and vascular shunting are almost invariable in ESLD. Low systemic vascular resistance (SVR) results in high cardiac output and high mixed venous oxygen saturationsIntrapulmonary & arteriovenous shunting Pulmonary hypertension may developTachycardia, bounding pulse ,Ejection systolic murmur

Pulmonary problems are both vascular and mechanical. Hepato-Pulmonary syndrome triad of end stage liver disease, A-a gradient >2 kPa , intrapulmonary vascular dilationImpaired pulmonary function in absence of cardiopulmonary diseaseImpaired 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.

Pulmonary changes

HEPATORENAL SYNDROME

Low GFR Low renal blood flow No other cause for renal failure Functional renal failure Symptoms water retention, Azotemia, hyponatremia, & oliguria

Hepatorenal failureCauses 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.

Managementof Hepato renal syndromeAvoid 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.

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

HAEMATOLOGICAL PROBLEMSAnaemia 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

GASTROINTESTINAL SYSTEMRupture of oesophageal varicesVassopressin & octreotide reduce portal hypertensionSusceptibility to infection - increasedDrug dispositionCholestasis 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

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

BENZODIAZEPINES-

Since diazepam & midazolam is metabolized by phase I reaction, hence recovery & elimination times in Cirrhotics.

OXAZEPAM & LORAZEPAM are safe in mild to moderate liver impairment.IV INDUCTION AGENTS-IV agentsChange in pharmacokinetics in cirrhoticsThiopentoneNo changePropofolProlonged recovery on infusionEtomidateProlonged elimination

MUSCLE RLAXANTS-

MUSCLE RLAXANTSAction in liver diseasesSChProlonged MivacuriumProlonged with infusionPancuronium/RocuroniumProlongedVecuroniumSlightly prolongedAtracurium/CisatracuriumUnchanged(safe)

Drugs metabolized by pseudocholinesIn 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.

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opioidsMorphine - prolonged elimination half-life, markedly increased bioavailability of orally administered morphine, decreased plasma protein binding, and potentially exaggerated sedative and respiratory-depressant effects.Mepridine - 50% decrease in clearance and doubling of half life.Fentanyl, sufentanyl, alfentanyl- highly lipid soluble, short acting (because of rapid redistribution to storage sites), almost exclusively metabolized in liver, hence 1st dose doesnt affect much but repeated top ups and continuous infusion may build up increase levels in tissues, decrease in elimination and prolonged effect. Remifentanyl- Remifentanyl has an ester linkage that allows for rapid hydrolysis by blood and tissue esterases; such hydrolysis leads to high clearance, rapid elimination, and recovery.

REMIFENTANYL IS IDEAL ANESTHETIC AGENT IN PT WITH SEVERE LIVER DISEASES82

VOLATILE ANESTHETICS

HALOTHANE-DIRECT EFFECTHBFIMMUNE MEDIATED INJURY

HALOTHANE ASSOCIATED HEPATITISAb to TFHMILD, SELF LIMITINGHEPATOTOXICITYMASSIVE HEPATICNECROSIS

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Halothane Hepatitis The incidence is 1:7000-30,000 halothane anaesthetics - higher in women, the middle aged and the obeseRarer in paediatric patients and with the newer volatile agents. Commonest iatrogenic cause of fulminant hepatic failureUnexplained liver damage within 28 days of halothane exposure in previously normal patient idiosyncratic reactionClinical features : malaise, anorexia,fever within 7 days ,jaundice within days to 4 weeks

ENFLURANE

Cross sensitivity with Halothane.

Can cause post operative jaundice in patients previously exposed to Halothane.

Read mechnism85

ANESTHETIC AGENTS & LIVER FUNCTIONS

Effects of Anesthesia on the Diseased Liveranesthesia results in moderate reduction in hepatic arterial blood flow and hepatic oxygen uptakeno clinical significance of these changes seen in healthy volunteers

liver blood flow returns to baseline during surgeryinitial hypoperfusion and/or reperfusion injury may contribute to postoperative liver dysfunction

Effects of Anesthesia on theDiseased LiverVolatile Anesthetics (Halothane & Enflurane)reduce hepatic arterial (HA) blood flow (systemic vasodilatation)small negative inotropic effectsignificant hepatic metabolism (halothane - 20%, enflurane - 3%)Isofluranemay actually increase HA blood flowpreferred agent in patients with liver diseaseundergo less hepatic metabolism (0.2%) (corresponds with lower risk of drug-induced hepatitis)

(risk of halothane hepatitis quite low: 1 in 35 000)

Effects of Anesthesia on theDiseased LiverHypercarbiasympathetic stimulation of splanchnic vasculature, thereby decreasing portal blood flowpCO2 should be maintained between 35-40 mmHg during surgery

Effects of Anesthesia on theDiseased LiverNeuromuscular Blocking Agentsprolonged in patients with liver disease due to:reduced plasma pseudocholinesterase activitydecreased biliary excretionincreased volume of distributionAtracuriumpreferred agent in patients with liver diseasemetabolism independent of the liverDoxacuriumlong-acting muscle relaxantrecommended for prolonged procedures including hepatic transplantation

Narcoticsmorphine and meperidinereduces hepatic blood flowfentanylpreferred narcotic agentSedativesdiazepamprolonged metabolism in patients with liver diseaselorazepameliminated by glucoronidation without hepatic metabolismpreferred agent

Estimating Operative Risk in Patients with Liver Diseaseminimal data on precise estimates of operative risk

most data from small retrospective studies of cirrhotic patients undergoing abdominal surgery

pre-operative risk likely dependent on type of underlying liver disease

Perioperative risks

Risk assesmentChild Pugh scoreMELD score > 18 yearsPELD score < 18 yearsGarrisons scoreDixon Freidman scoreKnodell Ishak score for chronic hepatitisASA ClassificationPOSSUM score

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Risk scoring systems

The Child-turcotte-Pugh scoring system

CHILD SCORE AND SURGERYChild A - safely undergo elective surgery.

Child B - may undergo elective surgery after optimisation with caution.

accepted criterion for listing to OLT. Child C - contraindication for elective surgery.

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Model for end stage liver disease(MELD)scoring system

MELD SCORE AND SURGERYMeld < 10 - safely undergo elective surgery.

Meld10 -15 - may undergo elective surgery after optimisation with caution.

accepted criterion for listing to OLT. Meld > 15 - contraindication for elective surgery.

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Histological activity index(knodell Ishak score) Periportal necrosis ( no necrosis to MLN)

Intralobular necrosis (no to marked necrosis)

Portal inflammation (none to marked infm)

Fibrosis (none to cirrhosis)Score 0-10

Score 0-4

Score 0-4

Score 0-4 total=22

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Garrison risk factors forcirrhosisGARRISON et al factors associated with increased post operative mortality S.albumin 10.000/cu.mm Treatment with more than two antibiotics S.bilirubin>3mg/dl PT>1.5sec over control Presence of ascities Malnutrition Emergency surgery

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Risk factors in obstructive jaundice DIXON FREIDMAN RISK FACTORS

S.Bilirubin > 11mg/dl Malignant obstruction Haematocrit < 30% Renal failure CholangitisHypoalbuminemia If at least 3 of above mortality 60% If none of above mortality 5%

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ASA physical status classificationASA I Normal healthy patient.ASA II Patient with mild systemic disease.ASA III Patient with severe systemic disease. but is not incapacitating.ASA IV Patient with severe systemic disease that is a constant threat to life.ASA V Moribund patient who is not expected to survive without the operation.ASA VI Brain dead patient.

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EXAMPLES FOR ASA CLASSESASA II - Cigarette smoking without COPD

More than minimal drinking

Mild obesity

Well controlled HT or DM without systemic or end organ involvement

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ASA III Morbid obesity Active hepatitis Chronic renal failure/ ESRD Mild COPD ( well controlled) Poorly controlled HT or DM with systemic involvement Stable angina, MI, CVA, CHF, coronary stent over 6 months ago Ejection fraction < 40 % EXAMPLES FOR ASA CLASSES

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ASA IV Hepatorenal syndrome Unstble angina, MI,CVA,Coronary stent of < 6 months duration Symptomatic CHF Ejection fraction < 25 % Moderate to severe COPD

ASA V - MODS/Sepsis with HD instability Poorly controlled coagulopathy EXAMPLES FOR ASA CLASSES

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ASA I & II - 0.3 %

ASA III - 4 to 5%

ASA IV - 25 to 30%

ASA V - > 70 % MORTALITY IN ASA SUBCLASS

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High risk factors for surgery A) Type of surgery Emergency > Elective Intraabdominal > Extraabddominal Upperabdomen > Intraabdomen Nonlaproscopic > laprascopic Emergency CT > Elective CT Hepatic resection with MELD score>8/CPS>6 Prior abdominal surgery

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High risk factors for surgery(cont) B) Characteristics of patient Child class C>B>A. Meld score > 15. High ASA status. S.bilirubin >3mg/dl(>11mg in obstructive LD). Malignant > Benign jaundice. S.Albumin 3 sec above control(not corrected with vit K) complication of cirrhosis(Ascites,GE Varices,HRS,HPS,PPHT Hydrothorax,Cardiomyopathy). Abnormal quantitative liver function tests.

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Optimisation before surgeryAscites to be drained before surgery if possible.Hydrothorax should be treated before surgery.Encephalopathy should be corrected before surgery.Anemia should be corrected before surgery.Coagulopathy should be corrected before surgery.Electrolyte imbalance should be corrected before the surgery.Nutrional needs should be addressed by either enteral or by parentral route before surgery.Alcohol abstinence for atleast 6 months is needed for elective suregery.Antiendotoxin measures to reduce the renal dysfunction. Coexisting illness( COPD, HT & DM) should be optimised.

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Effect of Type of Surgical Procedure on the Diseased Liver

important determinant of post-operative hepatic dysfunctionrisk: laparotomy > extra-abdominal surgerygreater reduction in HA blood flowcholecystectomy, gastric surgery and colectomy associated with high mortality rates in patients with decompensated cirrhosismorbidity/mortality higher for emergent than elective surgery

Contraindication for elective surgeryAcute viral hepatitisAcute alcoholic hepatitisFulminant hepatic failureSevere chronic hepatitisChild's class C cirrhosisSevere coagulopathy (pl count 50.000/mm3 & PT3s despite of vitamin k administration)Hypoxia(Po230% of hepatocytes containing fat)J Gastrointest Surg, 1998

period of abstinence from alcohol before surgery advisable

Other Causes of Liver DiseaseAutoimmune Hepatitisif in remission, elective surgery well tolerated in patients with compensated liver diseaseperioperative administration of stress doses of hydrocortisone indicated in patients taking prednisoneHemochromatosismonitoring of diabetes in perioperative periodassess for possibility of cardiomyopathyWilsons Diseaseneuropsychiatric involvement - interferes with consentD-pencillamine can impair wound healing - decrease dose in first 1-2 postoperative weeks

Cirrhosisretrospective studies have shown that perioperative mortality and morbidity rates correlate well with the Child-Turcotte-Pugh class of cirrhosisAlcoholic Cirrhosis (abdominal surgery): Mortality Rates19841997Childs A 10% 10%Childs B 31 30Childs C 76 82some studies have not confirmed predictive value of Childs classification, mainly due to few Childs C patientsAPACHE III can predict survival in cirrhotic patients admitted to an ICU; yet to be studied in cirrhotics undergoing surgery

Drugs in Liver failure Drugs Safe Caution Premedication Lorazepam OxazepamMidazolamDiazepam Induction agentsSingle dose all are safe Volatile agentsNitrous oxideIso/sevofluraneDesfluraneEnflurane

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Drugs in Liver failurea Safe Caution Muscle relaxantsAtracuriumcisatracurimSuxamethoniumPancuroniumVecuronium OpioidsFentanyl Sufentanil Remifentanil Remaining drug AnalgesicsParacetamolOther NSAIDLidocaineBupivacaine

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Resection for Hepatocellular Carcinoma (HCC)annual incidence of HCC 3 to 5%perioperative mortality rate for hepatic resection 3 to 16%postoperative morbidity rates as high as 60%5 year recurrence rates are as high as 100%5 year survival rates are no higher than 50%

Anaesthetic consideration forChronic HepatitisSurgical risk correlate with clinical features,biochemical features and histological severity of the disease.

Elective surgery has been reported to be safe in asymptomatic patient with mild-moderate chronic hepatitis.

Symptomatic and histological severe CH have increased surgical risk particularly if hepatic synthetic or excretory function is impaired,PHT if present or bridging/MLN necrosis is seen on liver biopsy.

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Anaesthetic consideration forChronic HepatitisChronic alcoholic patient should be abstinent from alcohol for atleast 6 mon to undergo elective procedure.

NASH not a contraindication for elective surgery ( >30% hepatocytes if contain fat increased mortality)

Hemochromatosis Evaluate for complication such as diabetes,hypothyrodism and cardiomyopathy.

Wilsons disease Antipsychiatric medication has to be continued(surgery can ppt or aggravate neurological symptoms).

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IV.Complication of Decompensated cirrhosisPortal HT - GE Varices PH gastropathy Hyperspleenism Ascites including SBP

Respiratory - HPS PPHT Hepatic hydrothorax

Haematological - Anaemia Thrombocytopenia (qualitative defect also present) Coagulopathy

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Complication of Decompensated cirrhosis(cont)Kidney - Hepatorenal syndrome

CVS - Cardiomyopathy

CNS - Hepatic encepalopathy

MSK - Osteoporosis Osteopenia

Nutrition - Malnutrition

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Respiratory systemVentilation-perfusion mismatch caused by impaired HPV,pleural effusion,ascites & diaphragm dysfunction.Decreases in diffusion capacity due to intersitial oedema,increased ECF & pulmonary HT.Incidence of coexisting pulmonary abnormalities Hepatic hydrothorax 5 to10% H.P.synrome - 40 to 50% PP hypertension - 4 to 6% ABG & PFT - 40 to 50%

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Anaesthetic consideration(R.S)Ascites fluid to be drained preoperatively with simultaneous colloid replacement to reduce the splinting effect.Coexistent COPD should be optimised & hydrothorax should be treated. Chest tube drain is C/I in hepatic hydrothorax.Increased risk for aspiaration(aspiration prophylaxis & rapid sequence induction).Avoid PEEP as far as possible.Avoid N2O in patient with COPD & PPH.Avoid hypoxia(High inspired 02) & hypocarbia.Response of OLT is poor in PPH when compared to HPS.Elective postoperative ventilation for major surgery.Extubation should be done when the patient is fully awake.HPS & hepatic hydrothorax if present is indication for OLT.

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Cardiovascular systemDecreased peripheral vascular resistance.Increased cardiac output.Increased blood volume but redistributed.Low- normal blood pressure with mildly elevated heart rate.Decreased effective circulatorary volume.Diminished response to catecholamines.Possible cirrhotic & alcoholic cardiomyopathy.

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Anaesthetic consideration(CVS)Pain and light plane of anaesthesia cause decreased HBF through sympathetic nervous system.

Hypotensive effect of volume depletion is exacerbated because of impaired vasoconstrictor response to catecholamines.

Redistribution of blood flow from splanchnic as well as Skeletal muscle to central circulation is also impaired.

Blunted vascular response to exogenous vasopressors and volume expansion.

Volume assessment and fluid management thro cvp are often misleading as cvp are often elevated despite relative hypovolumia from increased back pressure in the IVC from hepatic enlargement,scarring and ascites induced increased IA pressure.

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Anaesthetic consideration(CVS)PCWP/CVP guided fluid management.Low threshold for starting vasopressors as haemorrhage is poorly tolerated.Low threshold for volume overload as well as to v.presor induced pulmonary oedema.Propranolol if used for prophylaxis for GE varices may mask the signs of haemorrhage.Diuretics should be used with caution in ascites patient without oedema (protective effect from intersitial fluid wont be there as in patient with oedema).Cirrhotic cardiomyopathy if present is an indication for liver transplantation.

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Renal system Decreased renal perfusion and GFR.

Reduction in free water clearance.

Reduction in sodium excretion.

Hepatorenal syndrome occurs in 10% of patients with decompensated cirrhosis(100% mortality if OLT not done).

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Anaesthetic consideration( Kidney) Urea falsely low due to decrease hepatic production.

Bilirubin lowers the measured s.creatinine(underestimation of renal dysfunction)Renal function assesed by inulin ,125 I iothalamate or 51 cr- EDTA clearance.

Avoid aggressive diuretic therapy.(Precipitate HE & HRS)

Absence of response to spironolactone400mg/day & furosemide160mg/day indicates ascites becomes refractory (consider LVP or TIPS).

catheterise evening before surgery and start iv fluids while fasting @ 1- 2ml/kg/h to maintain u.o.of atleast 1ml/kg/hr.( to prevent HRS ) Avoid morning dose of diuretics before elective surgery.

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Kidney(cont)PCWP/CVP guided I.O.fluid management.

I.O chart in the P.O.period.

Avoid hypotension in the P.O.period (meanB.P.10-20% 0f preop value). U.O.of atleast1ml/kg/hr must be achieved in the I.O.period (if not mannitol or furosemide infusion).

Avoid NSAID & aminoglycosides in the I.O.period.

Cirrhotics are also at risk for ATN in the postoperativeperiod.

HRS if present is an indication for OLT.

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Gastrointestinal systemDevelopment of GE varices & spleenomegaly signify the development of portal hypertension.Development of ascites indicates the onset of hepatic decompensation.GE varices more likely to bleed if the portal vein pressure exceeds 12mmhg.Prognosis after development of ascites is poor.( 50% die within 3years from the onset of diagnosis)

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Anaesthetic consideration regardinggatroesophageal varicesBlood loss in GE varices is haemodynamically sgnft and patient should be managed in ICU.Propranolol used for prophylaxis will mask the signs or haemodymamic effects of haemorrhage.Airway should be protected to prevent the risk from aspiration.Crystalloid and colloid resuscitation along with the pharmacological measures such as vasopressin, somatostatin or octreotide.

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Alteast 8-12 units of blood should be crossmatched during the resucscitation period.FFP should be given if the PT is 1.5 times more than the control value.Care should be taken to prevent volume overload as the baseline SBP of most cirrhotics is 85 to 95mmhg (volume overload increases hge).Endoscopy should be done within 12hrs once the patient is haemodynamically stable. Anaesthetic consideration regardinggatroesophageal varices

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Ascites increases the risk of aspiration by increasing intra- abdominal pressure ( also decreased GITmotility & GERD due to hiatal hernia in the cirrhotics).PICD can be prevented by concurrent administration of salt poor albumin or other colloid.Ascites is said to be refractory if there is no response to the maximum dose of furosemide and spiranolactone.TIPS should be considered for patient with refractory ascites who is listed for OLT.Tense and refractory ascites should be drained adequately before surgery ( significant intra and postop comp.).

Anaesthetic consideration regardingascites

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Ascites Anaesthetic consideration PreoperativeRespiratory distressHypotension if inadeq replaced after LVPHepatic hydrothoraxRisk for SBP (50% mortality)IntraoperativeRisk for aspirationFalse high CVPHaemodynamic instabilitySplinting effect to diaphragmIncreased volume of distribution

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Postoperative - Wound dehiscence Abdominal wall herniation Atelectasis

1 litre of ascitic fluid = 50ml of 25% albumin( i.e 1 litre roughly contains 10gm of protein).

Albumin should be idealy used in case of LVP(>5L/day). Half of the albumin during the procedure and the other 6 hrs later. Ascites Anaesthetic consideration

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Haematological systemAnaemia is common with chronic liver disease.

Thrombocytopenia(qualitative as well).

Mild thrombocytopenia is often the first manifestation of worsening of fibrosis in patient with chronic hepatitis. Prothrombin time & partial thromboplastin time is prolonged (mild- moderate prolongation).

Fibrinogen level will be normal ( low fibrinogen level with severe thrombocytopenia R/O DIC ).

Drugs used to treat chronic hepatitis can cause anaemia. Rifampin Hemolytic anaemia

Interferon- bone marrow suppression

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Anaes.consideration(Haematology)Liver biopsy can be safely performed if plateletcount>50,000/mm3 and PT as well as APTT do not exceed 1.5 times the control value( BT not a reliable indicator). Avoid drugs that precipitate bleeding such as NSAID/ Warfarin.

Avoid IM injection to prevent haematoma.

Haematocrit should be maintained around 30% in the perioperative period.

Anaemia should corrected preoperatively preferably with packed cell or fresh whole blood ( Balanced against the risk of inducing HE from haemolysed RBC).

Thrombocytopenia in hyperspleenism as a rule is mild( severe thrombocytopenia indicates the development of DIC).

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Haematology (Cont)Thrombocytopenia if present should be preoperatively corrected.

Exploratory laprotomy>50,000/mm3

Closed space surgery>1Lakh/mm3

PT and APTT becomes abnormal only with severe deficiency of CF (abnormal with CF < 30% of normal level).

PT and APTT if prolonged should be corrected to be within 1.5times the control value.(Risk of Hge increases if PT & APTT exceeds 1.5 times the control value). Failure of PT and APTT to respond to vitK/FFP indicates poor prognosis.

FFP must be transfused just prior to procedure and repeated every 8-12hrs to maintain acceptable coagulation parameters( chance of volume overload- Exchange plasma transfusion).

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Haematology(cont)Adequate blood/ blood component should be arranged prior to surgery.

Invasive arterial BP preferable than NIBP(repeated NIBP cause bruises).

Blood loss should be closely monitored &should be corrected immedietly (Hematocrit maintained around 30%). FFP should be given when crystalloid,colloid or packed cells are given to replace blood loss.( 1unit FFP=1unit packed cells=250ml crystalloid)

Hypothermia should be avoided (humidified gases,warm ivf,warming blankets,forced air warming devices & blood warmer).

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Haematology(cont)Blood loss can be minimised by perioperative administration of tranexemic acid (prostate & ortho surgeries).

Correct/prevent I.O. factors that increases bleeding(dilution,hpypothermia hypocalcemia & acidosis).

Thromboelastography for I.O. assesment of coagulation parameters.

Universal precautions in patients with hepatitis (30% - HepB & 3% -HepC)

Even 0.04ml blood may be enough to infect an anaesthesiologist.

RA not contraindicated if coagulation parameters are within normal.

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Causes of bleeding in liver diseaseAnatomical factors gastroesophageal varices peptic ulcer gastritis haemoorhoid Thrombocytopenia Hepatic function abnormalities

Decreased synthesis of procoagulant protein

Decreased synthesis of coagulation inhibitors

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Causes of bleeding in liver disease(cont) Failure to clear activated coagulation factors

Impaired absorbtion and metabolism of vit k

Synthesis of abnormal fibrinogen

Intraoperative factors Hypothermia Dilution Hypocalcemia Acidosis

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Platelet count. >100000/mm safe 70,000-100000 - safe if cg scn is wnl 1.5 - unsafeActivated partial thromboplastin time APTT>40sec -unsafe Coagulation parameters and neuraxial block

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Neuraxial anaesthesia(cont) Epidural preferred than spinal anaesthesia. LA dose should be titrated.(flow limited drug) Hypotension more likely with high spinal( T4 level 20% decrease in HBF) but safe for lower limb procedures. Strict aseptic precautions increased susceptiblity for infection. Epidural Useful for postopanalgesia/decreases P.O pulmonary complication.

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Anaesthetic consideration inobstructive jaundiceIt includes Coagulopathy Endotoxemia Haemodynamic instability Renal failure Altered drug handling due to cholestasis Impaired wound healing.

Measures taken to to reduce the renal failure is responsive better in benign rather than malign condition.In malignancy only way to reduce the incidence of renal failure is to maintain adequate iv volume and perfusion pressure.

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Effect of obstructive jaundice on thecardivascular system Negative inotropic effect by bile salt.

Negative chronotropic effect by bile salt.

Altered haemodynamic response to haemorrhage.

Blunted vascular response to vasopressor and volume expansion.

Jaundiced induced cardiomyopathy.

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Haemodynamic instability caused by the bile salts & endotoxin on the cardovascular function.Diuretic and the natriuretic effect of bile salt.Reduced renal perfusion because of enhanced renal vascular reactivity to endogenous vasopressors.Direct nephrotoxic effect by bile salt and conjugated bilirubin (controversial)Renal tubule blockade of bilirubin cast may further potentiate the renal injury. Effect of obstructive jaundice on theRenal function

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Measures to prevent perioperativerenal failureMaintainence of adequate iv volume( most important of all the measures).Avoid NSAID & AMINOGLCOSIDES.Oral lactulose/ ursodeoxycholic acid.Endoscopic internal biliary drainage.Preoperative and postoperative mannitol if the Bn>8mg per dl (controversial role). Dopamine/ furosemide has no role.

Except for maintainence of adequate iv volume and avoidance of NSAID, all other measures are controversial in malignant jaundice.

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Antiendotoxin measuresAvoid oral antibiotics.Avoid percutaneous external drainage.Oral lactulose.Oral ursodeoxycholic acid.Endoscopic internal biliary drainage.

Experimental drugs Taurolidine Rifaximin Polymyxin.

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Preoperative evaluationComplete history with clinical examination.Investigation.Risk assesment.Management of complication due to liver disease.Preoperative optimisation of modifiable risk factors in Child B status patient and obstructive jaundice.Premedication and instruction before surgery(include the informed high risk consent).

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Preoperative investigationHaematological Blood grouping/typing Haemoglobin/ HCT WBC count Platelet count Bleeding Time PT / INR APTTLiver function tests.

Serology for viral hepatitis.

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Preoperative investigation(cont)Metabolic / Renal Blood glucose S.Electrolytes / S.Calcium Blood urea S.Creatinine U.ElectrolytesCardiorespiratory Chest x-ray ECG ECHO ( if needed) PFT/ABG ( if needed) .

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Ascites TreatmentSalt restriction

Fluid restriction

spiranolactone

Furosemide

Albumin Not > 2 gm per day

800-1000ml/day if serum sodium < 125meq/L Dose 100mg per day (max dose 400mg)Dose 40mg per day (max dose 160mg)8-10g/L of fluid removed (if > 5L removed)

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Coagulopathy TreatmentVit K 10 mg sc or slow iv over 20 minutes for 3 days(altered PT due to vit K def if there is 30% improvement in the first 24 hours).FFP in case of emergency rapid correction or in vit K unresponsive patients.Platelet transfusion in case of thrombocytopenia.Cryoprecipitate if fibrinogen 12 minutes.

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Hepatic encephalopathy treatmentCare of airway,haemodynamic,metabolic and acid base status.Identify and correct precipitating factors.Restriction of protein from the diet.Avoid narcotics and sedatives.Reduction of blood ammonia by lactulose and neomycin.

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Premedication Oral premedication preffered than intramuscular. HE absent lora / oxazepam (small dose) HE present - avoid sedativeAspiration prophylaxis.

Vit k slow iv continue till morning of surgery.

FFP should be given immedietly before surgery.

Mannitol infusion if bilirubin > 8mg/dl

Steroidal supplemenation in autoimmune hepatitis.

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Premedication Antipyschotic medication to be continued in pt with wilsons disease.

Continue other optimisation measures for ascites ,HE etc except for morning dose of diuretics.

Large bore iv cannulae with cvp line after excluding coagulopathy.

Catheterise evening before surgery and start iv fluids @1-2ml/kg/hr while fasting to maintain u.o. of atleast 1ml/kg/ hr.

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Induction agents All the induction agents (single dose) are safe. Dose has to be reduced and given slowly except in alcoholics with compensated liver disease. Haemodynamically stable - thiopentone/propofol

Haemoynamically unstable - ketamine/etomidate

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Inhalational agentsHalothane & Enflurane has to be avoided because of its effect on hepatic blood fow and its metabolism.

Maintainence with Isoflurane-O2-N20 / isoflurane O2 and fentanyl or remifentanyl if N20 has to be avoided.

PEEP may have to be given to prevent hypoxemia but care should be taken to maintain C.O & B.P.

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Muscle relaxantsMuscle relaxants

Suxamethonium single dose doesnt need dose reduction.

Maintaince with Atracurium in titrated doses under neuromuscular monitoring if available.

Loading dose larger than normal but the maintainence dose is smaller than normal. Reversal can be given for minor procedures but for major procedures elective postoperative ventilation is often needed.

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Intraoperative considerationsGoal is to maintain the adequate blood flow and oxygen content in the blood so as to maintain the oxygen supply demand relation in the liver. High inspired O2 to prevent hypoexemia.Maintainence of adequate cardiac output and B.P.(PCWP/CVP guided fluid management) Avoid hepatotoxic drug / NSAID.Avoidance of relative overdose of anaesthetics.Maintainence of normocarbia and normothermia.Maintainence of adequate haematocrit.Adequate blood & volume replacement to prevent hypotension.Monitoring of u.o/coag parameters/glucose/calcium and electrolytes.

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Intraoperative monitoring and equipmentPulse oximetry

NIBP/INVASIVE B.P.

Electrocardiography

PCWP/ CVP

ETCO2

TemperatureNM monitoring

Urine output

Blood loss(swab,suction,drape & floor)Input output

Rapid infusion system

Forced air warmers

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Biochemical/HaematologicalMonitoringHaematocrit

Serum electrolytes / ionised calcium

Blood glucose

Arterial blood gas analysis

Coagulation parameters / TEG

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Postoperative managementPatient with child B grade who has undergone a major surgery should be shifted to ICU and may need to be electively ventilated.Fluid , electrolyte, acid base balance, coagulation parameters temperature, u.o and cvs stability should be maintained like that of i.o.period.Sedation and pain medication should be carefully titrated.Chest x-ray should be immedietly taken to see the lung fields and to check central as well as pulmonary catheter.Monitor the patient for features of hepatic decompensation.

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Postoperative Periodmonitor for signs of liver decompensation including worsening jaundice, encephalopathy and ascitesbilirubin and prothrombin time best measures of hepatic functionrenal function important to monitor because of the risk of hepatorenal syndromemonitoring of serum glucose levels as hypoglycemia often accompanies postoperative hepatic failure

Sources of this lecture:HEPATIC ANATOMY,PHYSIOLOGY & ANESTHETIC EFFECTS, Dr. Mohd Saif Khan MD ,LHMC, New DelhiRISK OF SURGERY IN THE PATIENT WITH LIVER DISEASE, Ajay Jain,Gastroenterology Fellow ,January 16, 2002.ANAESTHESIA AND LIVER DISEASES, DR.D.KIRUBAKARAN,2011.08.08Dr. C.K. Pandey,new delhi, anesthetic consideration and perioperative risks in patient with liver disease.