HEPATIC -STUDENT.pdf

ANESTHESIA AND THE LIVER NRAN 80516 SUMMER 2024 RON ANDERSON, M.D. KEY POINTS Intrinsic regulation of hepatic arterial blood flow occurs via two mechanisms, metabolic regulation and the hepatic buffer response. Have an in-depth understanding of the critical functions of the liver. In the healthy liv...

ANESTHESIA AND THE LIVER NRAN 80516 SUMMER 2024 RON ANDERSON, M.D. KEY POINTS Intrinsic regulation of hepatic arterial blood flow occurs via two mechanisms, metabolic regulation and the hepatic buffer response. Have an in-depth understanding of the critical functions of the liver. In the healthy liver, 80% of hepatic blood volume (400-500 ml) can be transferred to central circulation within seconds. PT may be a useful monitor in acute liver failure as occurs following hepatotoxic drugs due to the short half-life of liver derived Factor VII. HCV is the most common blood-borne infection in the U.S., accounting for 40% of chronic liver disease. Advanced cirrhosis affects nearly every organ system in the body. Of the volatile anesthetics, sevoflurane best preserves hepatic blood flow and oxygenation. KEY POINTS Know the risk factors and prognostic indicators for halothane hepatitis. Understand the consequences of portal hypertension. Acute hepatic disease, regardless of the etiology, increases perioperative morbidity and mortality, and elective surgery should be delayed. If appropriate, careful titration of induction agents is preferred with significant liver disease. Increased concentration of vasodilatory substances such as glucagon, may result in markedly reduced response to catecholamines. Understand the pathophysiology of hepatorenal syndrome. 3 OUTLINE BLOOD SUPPLY FUNCTIONS ASSESSMENT OF FUNCTION DISEASE PROCESSES PERIOPERATIVE MANAGEMENT POSTOPERATIVE CONSIDERATIONS 4 HEPATIC BLOOD SUPPLY HEPATIC ARTERY PORTAL VEIN REGULATION OF BLOOD FLOW INTRINSIC HEPATIC BUFFER RESPONSE EXTRINSIC NEURAL HUMORAL 5 HEPATIC BLOOD SUPPLY ~ 25% of cardiac output Hepatic artery – 25% of blood supply – 50% of Oxygen supply Portal vein – 75% of blood supply – 50% of Oxygen supply 6 TRIBUTARIES OF PORTAL VEIN Inferior mesenteric vein Superior mesenteric vein Splenic vein – Pancreatic veins Gastric vein Esophageal vein Inferior mesenteric vein Superior mesenteric vein Splenic vein Pancreatic veins Gastric vein Esophageal vein Consider consequences of portal hypertension. Consider consequences of portal hypertension. 7 REGULATION OF HEPATIC BLOOD FLOW Designed to serve two demands: – Adequate oxygen and substrate for the liver’s needs – To allow the liver to serve it’s purposes for the rest of the body Intrinsic regulation – Regional microvascular Extrinsic – Neural – Humoral 8 INTRINSIC REGULATION Regulation of portal venous flow – None Regulation of hepatic arterial flow – Hepatic buffer mechanism Increase in hepatic artery flow in response to decreased portal vein flow Maximum response is ~100% increase in hepatic artery flow in response to a 50% decrease in portal vein flow. May be diminished or abolished by splanchnic hypoperfusion or endotoxemia. – Metabolic regulation Decreased portal blood pH and O2 content or increased PCO2 cause an increase in hepatic artery blood flow. Most active in the postprandial state, much less so in the fasted state. 9 HEPATIC BUFFER RESPONSE PORTAL VENULE HEPATIC ARTERIOLE ADENOSINE 10 EXTRINSIC REGULATION - NEURAL Portal venous pressure dependent on: – Splanchnic arteriolar tone – Portal venules – Post-sinusoidal tone Hepatic venules Stimulation of α1 receptors increases vascular tone: – Reduced blood flow – Reduced blood volume 11 EXTRINSIC REGULATION - HUMORAL Epinephrine and norepinephrine – Much greater effect than dopamine(insignificant) – Hepatic arterial beds contain both αand β adrenergic receptors – Portal venous beds contain only α receptors Glucagon – Produces long-lasting arteriolar dilation – Antagonizes arterial constriction from other responses Angiotensin II – Marked constriction of arterial and portal vasculature Reduced mesenteric outflow Reduced total hepatic blood flow Vasopressin – Intense vasoconstriction of splanchnic arterial vessels while decreasing portal venous resistance , causing marked decrease in portal vein blood flow. – Useful in high doses to reduce portal hypertension and reduce esophageal variceal bleeding. 12 HEPATIC INNERVATION Sympathetics predominate over parasympathetics Sympathetic stimulation – Hepatic vascular resistance increases – Hepatic blood volume decreases – Blood glucose increases Increased gluconeogenesis Increased glycogenolysis Parasympathetic innervation – Blood glucose decreases Increases glycogen synthesis Increases glucoses uptake 13 HEPATIC FUNCTIONS BLOOD RESERVOIR COAGULATION ENDOCRINE BILIRUBIN EXCRETION METABOLIC PROTEIN SYNTHESIS IMMUNOLOGIC DRUG METABOLISM 14 BLOOD RESERVOIR Contains 10–15% of the total blood volume Intense sympathetic stimulation produces a rapid reduction in hepatic: – Blood flow – Blood volume 80% of hepatic blood volume (400-500 ml) can be transferred to central circulation within seconds. Suppression of the sympathetic nervous system by anesthetic agents attenuates this response and predisposes the patient to circulatory decompensation. Impaired vasoconstrictive responses due to severe liver disease also exacerbates hypotension from hypovolemia. 15 COAGULATION Liver synthesizes all coagulation factors except: – III – IV – vonWillebrand factor Liver synthesizes precursor proteins for vitamin K dependent factors: – II, VII, IX, X Synthesizes thrombopoietin, thereby modulating platelet production. Produces modulators of fibrinolysis and clotting: – Antithrombin III, proteins C and S, and fibrinolytic factors Liver is therefore important not only in production of clotting factors, but in modulating their consumption. 16 PT/ INR AS A MONITOR OF LIVER FUNCTION Liver-derived coagulation factors have short T1/2 Shortest is Factor VII with a T1/2 of ~ 4 hours. PT may therefore be a useful monitor in acute liver failure as occurs following hepatotoxic drugs. Failure of normalization of PT/ INR following vitamin K administration in a patient who had been on coumadin may indicate underlying hepatic dysfunction. 17 ENDOCRINE FUNCTION Synthesis and secretion: – IGF-1 (Insulin-like growth factor-1) – Angiotensinogen – Thrombopoietin Biotransformation – Conversion of T4 to T3 Inactivation – – – – – Corticosteroids Aldosterone Estrogen, androgens Insulin Anti-diuretic hormone 18 BILIRUBIN EXCRETION Bilirubin is the end product of heme degradation – ~75% derived from hemoglobin breakdown Steps: 1. 2. 3. 4. 5. Bilirubin bound to albumin and transported to liver. In liver, albumin removed from unconjugated bilirubin. Bilirubin conjugated primarily with glucuronic acid. Conjugated bilirubin excreted into bile. Passes into intestine, converted to urobilinogen and excreted. 6. ~10% absorbed in intestine and returns to liver via portal vein, where it is sent back through bile to small intestine. 19 METABOLIC FUNCTIONS Carbohydrate metabolism – Dietary carbohydrate arrives in liver via portal vein. – Postprandial Insulin mediated hepatic extraction of glucose from the portal blood Excess glucose converted to glycogen – Liver can store ~ 75 grams of glycogen (~24 hrs of glucose need) – Fasting Initially glucagon mediated glycogen breakdown Then, muscle and fat catabolism and gluconeogenesis 20 HYPER and HYPOGLYCEMIA IN LIVER DISEASE Chronic liver disease – Hyperglycemia primarily due to: Portosystemic shunting – Hypoglycemia more common in advanced disease due to: Impaired glycogen storage Impaired glycogenolysis Impaired gluconeogenesis Also seen with large hepatocellular CA due to increased glucose uptake by tumor 21 LIPID METABOLISM Synthesis of fatty acids from excess: – Carbohydrate – Protein – Lipid Esterification of fatty acids to: – Triglycerides – Cholesterol – Phospholipids Packaging into lipoproteins for transport to adipocytes. 22 AMINO ACID METABOLISM Liver is capable of synthesizing the non-essential amino acids. Proteins degraded to amino acids in hepatic lysosomes. Amino acids then: – Used for glucose production – Used in lipid metabolism – Further deaminated to keto-acids, glutamine, or ammonia. Ammonia converted to urea which is then excreted by the kidneys. – Failure of ammonia degradation in liver failure leads to increasing serum ammonia levels and hepatic encephalopathy. 23 PROTEIN SYNTHESIS Albumin – 10% of the protein produced by the liver – 60% of total plasma protein Primary determinant of colloid oncotic pressure – Important transport mechanism – Binds many anesthetic drugs – T1/2 ~ 20 days Psuedocholinesterase – Manufactured in liver – Required for degradation of: Succinylcholine Mivacurium Ester local anesthetics 24 IMMUNOLOGIC FUNCTION Kupffer cells – ~10% of hepatic mass – Tissue macrophages which filter toxins, bacteria and debris from the GI tract. Impairment of Kupffer cell function is often a precursor to sepsis and multi-organ failure, particularly following splanchnic ischemia or severe GI pathology. 25 DRUG METABOLISM Synthesis of drug-binding proteins which: – Effect apparent volume of distribution of drugs – Act as sinks to decrease free drug concentration Hepatic Clearance – The sum of all processes used by liver to eliminate a drug from the body Hepatic Biotransformation – Metabolism of drug by hepatocytes into inactive, water-soluble substances for excretion in urine or bile 26 DRUG METABOLISM Phase I reactions – Render the drug more polar via: Oxidation Reduction N-dealkylation – Most involve cytochrome P450 enzymes Phase II reactions – Water solubility of the compound is enhanced – Requires transferase enzymes 27 DRUG METABOLISM Intrinsic Clearance – Fraction of drug metabolized or “extracted” during a single pass through the liver – Basis of classification of drugs as having low to high hepatic extraction ratios High Hepatic Extraction Ratio – Clearance determined by hepatic blood flow Low Hepatic Extraction Ratio – Clearance relatively independent of hepatic blood flow – Clearance much more effected by increased free fraction (e.g. hypoalbuminemia) 28 EFFECT OF HEPATIC EXTRACTION RATIO ON DRUG CLEARANCE 29 HEPATIC EXTRACTION RATIOS OF COMMON DRUGS Low Extraction Alfentanil Diazepam Lorazepam Methadone Phenytoin Theophyline Thiopental Warfarin Intermediate Methohiexital Midazolam Vecuronium Adapted from Clinical Anesthesia – 3rd Edition Barash, Cullen, Stoelting High Extraction Bupivicaine Diltiazem Etomidate Fentanyl Ketamine Labetalol Lidocaine Meperidine Metoprolol Morphine Naloxone Propofol Propranolol Sufentanil Verapamil SUMMARY OF DRUG CLEARANCE IN HEPATIC DISEASE Reduced hepatic blood flow: – Prolongs the T1/2 and increases effects of high HER drugs. – May require significant dosage reduction. Hypoalbuminemia results in increased concentration of free drug resulting in: – Increased drug effect – More rapid clearance of low HER drugs Volume of distribution of some drugs will be increased with hypoalbuminemia and ascites. Portosystemic shunting allows orally administered drugs to partially bypass the liver, resulting in: – Increased systemic effect – Prolonged duration of action. Bottom Line: – Careful drug titration is critical. 31 ASSESSMENT OF FUNCTION LABORATORY HEPATOCELLULAR DAMAGE HEPATOBILIARY DYSFUNCTION HEPATIC SYNTHETIC DYSFUNCTION BLOOD FLOW AND METABOLIC FUNCTION IMAGING BIOPSY 32 LABORATORY ASSESSMENT Liver Function Tests don’t give a diagnosis of a specific hepatic disease, but can identify a category of dysfunction: – Hepatocellular – Hepatobiliary – Hepatic synthesis Some are useful in prognosis and monitoring progression of disease. Others are not. 33 HEPATOCELLULAR DAMAGE Transaminases – AST (SGOT) Located in many tissues (heart, muscle, kidney, brain) – ALT (SGPT) Primarily in liver – Mild elevations ( 2 typical in alcoholic liver disease – AST/ALT < 1 more commonly in viral hepatitis 35 HEPATOCELLULAR DAMAGE LDH – May see high levels with hepatocellular necrosis, but has very low specificity for liver disease. – Not particularly useful GST – Found in many tissues, but isoenzyme B specific to liver. – Short T1/2 = 90 minutes makes it a useful marker of progression or resolution of injury. – Found in highest concentrations in centrolobular (zone 3) hepatocytes, which are most susceptible to ischemic injury and toxic drug metabolites. 36 HEPATOBILIARY OBSTRUCTION Alkaline phosphatase – Found in many organs, primarily liver and bone in healthy people – Obstruction to bile flow suggested by elevation of AP disproportionate to AST and ALT levels. – May be elevated during normal pregnancy – 5’-Nucleotidase (5’NT) An alkaline phosphatase specific to liver disease, so used to assess whether an elevated AP is of hepatic origin. GGT – Most sensitive test for biliary tract disease, but found in so many tissue it lacks specificity – Largely replaced by 5’NT 37 HEPATOBILIARY OBSTRUCTION Bilirubin levels assess: – Severity of jaundice – Extent of conjugation Unconjugated – 1 – 4 mg/dl » Excessive production e.g. hemolysis » Defective conjugation – > 5 mg/dl » Liver disease Conjugated – Impaired hepatic excretion – Extrahepatic obstruction – > 35 mg/dl renal failure compounding the problem 38 EVALUATION OF LIVER FUNCTION TESTS STOELTING 39 HEPATIC SYNTHETIC FUNCTION Typically measured with serum albumin and PT/INR – Albumin – T1/2 ~ 20 days Decreasing serum albumin levels in the absence of some other cause, e.g. burns, nephrotic syndrome, poor nutrition, fluid retention, etc implies a worsening of chronic liver disease. – PT/INR – T1/2 of Factor VII ~ 4 hours Short half life makes this a useful marker in acute hepatocellular injury May not see a change with mild or even moderate liver injury 40 BLOOD FLOW AND METABOLIC CAPACITY Indocyanine Green dye – Highly extracted by the liver so used as a test of hepatic perfusion and hepatocellular function. Metabolism of lidocaine to MEGX – MEGX concentration is measured 15 – 30 minutes following intravenous lidocaine. 41 HEPATIC IMAGING Ultrasound – Primary screening test for: Hepatic disease Cholelithiasis Biliary tract disease – Best technique for diagnosis of: Cholelithiasis Biliary tract obstruction CT – Better anatomic definition than USG – $$$ 42 ERCP Endoscopic Retrograde CholangioPancreatography – Endoscopic guidance of a catheter through the ampulla of Vater to inject contrast into the pancreatic duct and common bile duct. – Technique of choice when choledocholithiasis is suspected because a sphincterotomy can usually be done and a stone removed. 43 LIVER BIOPSY Only way to know the specific nature of hepatic damage May be useful in determining treatment protocol in Hepatitis C Useful to determine etiology of abnormal LFTs following liver transplant Technique: – Percutaneous – contraindicated with: platelets < 60,000 PT more than 3 seconds > control – Transjugular – safer with above coag abnormalities – Open PREVALENCE PARENCHYMAL DISEASE – VIRAL HEPATITIS – TOXIN & DRUG INDUCED – NON-PHARMACOLOGIC INDUCED – CHRONIC HEPATITIS VIRAL FATTY LIVER DISEASE ALCOHOLIC LIVER DISEASE – CIRRHOSIS – HEPATOCELLULAR CARCINOMA – PREGNANCY RELATED CHOLESTATIC DISEASE 45 PREVALENCE OF HEPATOBILIARY DISEASE ~10% of Americans (25 million) have some form of hepatobiliary disease Hepatitis B & C ~ 5 million Up to 50% of those with Hepatitis C may go on to develop cirrhosis 10 – 15% of those who consume large amounts of alcohol will develop severe alcoholic liver disease 46 PARENCHYMAL DISEASE Viral Hepatitis – Acute viral hepatitis reported in United States: HAV ~ 20% HBV ~ 50% HCV ~ 30% HDV HEV – HCV Most common blood-borne infection in the U.S. Accounts for 40% of chronic liver disease 47 VIRAL HEPATITIS STOELTING 48 TOXIN & DRUG INDUCED HEPATITIS Predictable, dose-dependent toxicity: – Acetaminophen – Carbon tetrachloride – Amanita phalloides (mushroom) Infrequent, unpredictable, not dose-dependent: – – – – – NSAIDs Volatile anesthetics Antibiotics Antihypertensives Anticonvulsants 49 VOLATILE ANESTHETIC ASSOCIATED HEPATITIS Most commonly associated with Halothane – Retrospective review of 856,000 halothane anesthetics from 1959 -1962: 1/35,000 – fulminant hepatitis leading to death 1/3,000 - nonfatal hepatitis – Risk Factors: Prior exposure to halothane – 10x more frequent in those with multiple exposures Female sex Obesity Hispanic Adulthood – Most cases in patients > 50 years of age. – Children very resistant. When seen, occurs following multiple exposures. 50 VOLATILE ANESTHETICS AND HEPATITIS BARASH 51 HALOTHANE HEPATITIS Classic presentation – Fever, chills, anorexia, nausea, myalgias, and rash followed by: – Jaundice 3–6 days later Predictors of a poor prognosis: – Overt jaundice – Age > 40 – Obesity Idiosyncratic – Affects only a very small percentage of those exposed – Incidence and severity unrelated to dose 52 CLUES TO THE MECHANISM OF HALOTHANE HEPATITIS Idiosyncratic Prior exposure Delayed onset Antibody production Typically accompanied by: – Eosinophilia – Circulating immune complexes – Antibodies that bind to antigens from halothane-treated rabbits Occupational exposure – Pediatric anesthesiologists have higher serum autoantibodies of this particular type than controls – Levels even higher in female pediatric anesthesiologists – No reports of halothane hepatitis from occupational exposure 53 VOLATILE ANESTHETICS AND HEPATIC BLOOD FLOW Halothane (BAD) – Most cardiovascular and respiratory depression – Greatest reduction in hepatic arterial flow Desflurane (???) – Marked reductions (~30%) in hepatic blood flow – May decrease splanchnic and hepatic oxygen reserves Isoflurane (GOOD) – Hepatic blood flow and oxygenation well preserved Sevoflurane (BEST) – Preserves blood flow and oxygen delivery to liver – Hepatic arterial buffer system remains intact* – Less reactive metabolic products 54 EFFECT OF VOLATILE ANESTHETICS ON HEPATIC BLOOD FLOW MILLER 55 EFFECT OF VOLATILE ANESTHETICS ON HEPATIC OXYGEN DELIVERY MILLER 56 NITROUS OXIDE “No convincing evidence that nitrous oxide causes hepatic toxicity in the absence of a precarious oxygen supply-demand ratio in the liver”. BUT – N2O increases sympathetic nervous system tone, so may slightly reduce hepatic arterial and portal venous flow. – N2O inhibits methionine synthetase potentially producing toxic effects in the liver. – Survey of 60,000 dentists and dental assistants found a 1.7-fold increase in liver disease. 57 OTHER ANESTHETIC AGENTS Ketamine produces a dose-dependent increase in markers of hepatic injury. Mechanism: – Sympathomimetic vs. – Direct hepatotoxicity – Altered hepatic metabolism Thiopental – At doses >750 mg may cause some hepatic dysfunction Other induction agents appear to be safe Opioids – No significant effect on liver if hepatic blood flow and oxygenation remain normal. – Sphincter of Oddi spasm 58 NON-PHARMACOLOGIC CAUSES Sepsis and Inflammation – Hypovolemia and splanchnic hypoperfusion – Large bacterial, endotoxin, and inflammatory cytokine load on liver, particularly with abdominal sepsis. – Impairment of hepatic arterial buffer response Hypoxia and Ischemia – Liver is extremely sensitive to hypoxic insult – Inadequate systemic perfusion can result in ischemic hepatitis 59 SURGICAL STRESS AND HEPATIC PERFUSION Surgical stress in general produces: – Sympathetic nervous system stimulation – Release of vasopressin – Activation of the renin-angiotensin-aldosterone system Laparotomy – Produces marked vasoconstriction , reducing splanchnic and hepatic blood flow Laparoscopy – Decreased surgical stress response, but: – Pneumoperitoneum decreases splanchnic and hepatic flow Cardiac Bypass – Bad Low-flow, non-pulsatile perfusion Catecholamine usage – Good Hypothermia Hepatic arterial buffer response helps maintain blood flow 60 CHRONIC HEPATITIS Chronic implies hepatic inflammation and necrosis for > 6 months Classified based on – Cause – based on serologic testing – Grade – degree of necrosis and inflammation – Stage – degree of fibrosis Viral – 85% of untreated, acute HCV progresses to chronic HCV 1.8% of U.S. population Most common indication for liver transplantation 61 CHRONIC HEPATITIS (cont) Fatty liver disease (non-alcoholic)(NAFLD) – – – – Most common cause of chronic liver disease in U.S. Up to 24% of Americans have NAFLD Defined as fat accumulation in liver > 5% by weight Risk Factors: Obesity - (70%) in consecutive autopsy study Type II diabetes – estimated at (75%) – Most patients asymptomatic – Some go on to develop cirrhosis 62 CHRONIC HEPATITIS (cont) Alcoholic liver disease – Three types: Fatty liver (steatosis) – May develop after even a brief period of heavy alcohol intake – Typically benign and resolves Alcoholic hepatitis – – – – Precursor of cirrhosis Up to 10-fold increase of aminotransferases AST typically higher than ALT Treatment = abstinence, bed rest, adequate nutrition Cirrhosis Alcohol abusers have a 2-3x increase in perioperative morbidity 63 EFFECT OF ALCOHOL ABUSE ON SURGICAL OUTCOME BARASH 64 CIRRHOSIS Affects more than 3 million in U.S. 12th leading cause of death Most frequent etiologies: – Hepatitis C – Alcohol abuse Symptoms: – Anorexia, weakness, N/V, abdominal pain Signs: – Hepatosplenomegaly, ascites, jaundice, spider nevi, encephalopathy Advanced cirrhosis affects nearly every organ system in the body. 65 CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Cardiovascular – – – – – – – Hyperdynamic circulation Decreased peripheral vascular resistance Low to normal arterial blood pressure Normal to increased stroke volume Normal filling pressures Mildly increased heart rate Total blood volume increased Alcoholic liver disease and hemochromatosis, two causes of cirrhosis can also result in cardiomyopathy. 66 CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Portal Hypertension – Hallmark of end-stage cirrhosis Increased vascular resistance to portal blood flow Increased portal venous inflow from dilated splanchnic arterioles Increased portal venous pressure and subsequent development of portosystemic collaterals and shunting. Majority of portal venous blood bypassing the liver. Hepatic oxygenation maintained by hepatic arterial buffer response 67 CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Consequences of Portosystemic Shunting – Esophageal varices – Hepatic encephalopathy – Altered drug metabolism – Susceptibility to bacterial infection – Ascites – Splenomegaly 68 CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Gastroesophageal Varices – – – – Present in ~50% of cirrhotics ~ 1/3 of these will bleed ~30% of initial bleeds are fatal Most will rebleed Management – – – – Fluid resuscitation/ blood replacement Airway protection Octreotide (synthetic somatostatin) ~ 80% effective Endoscopic band ligation or sclerotherapy ~90% effective – TIPS 69 TIPS PROCEDURE TRANSJUGULAR INTRAHEPATIC PORTAL SYSTEMIC SHUNT MILLER 70 CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Pulmonary Dysfunction – multifactorial – – – – Interstitial and airway edema Mechanical effects of ascites Pleural effusions Hepatopulmonary Syndrome – Triad of: Chronic liver disease Increased alveolar-arterial oxygen gradient IntraPulmonary Vascular Dilatations (IPVDs) – Vascular dilatations resulting in arteriovenous communications and hypoxia 71 CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Ascites – Most common major complication in cirrhosis 50% develop ascites within 10 years – 50% of cirrhotics with ascites die within 3 years – Pathogenesis poorly understood, but involves Na+ and water retention Two main theories: – Arterial underfilling hypothesis – Overflow hypothesis – Management: Na+ restriction and gentle diuresis Paracentesis Peritoneal-venous shunt TIPS Transplant 72 ASCITES THEORIES ????? 73 BARASH CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Spontaneous Bacterial Peritonitis – Develops 20 translocation of bacteria from the intestines to lymph nodes and subsequent bacteremia. – Treatment: Cefotaxime (3rd generation cephalosporin) Plus long-term antibiotic prophylaxis – Renal dysfunction develops in ~ 1/3 of cases – Mortality 54% with renal dysfunction 9% without renal dysfunction 74 CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Renal Dysfunction – Three main problems Decreased Na+ excretion Ascites Reduced free water excretion Decreased renal perfusion and GFR Hepatorenal Syndrome Hepatorenal Syndrome – – – – Intense renal vasoconstriction Low GFR Preserved renal tubular function Normal renal histology 75 CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Pathophysiology of hepatorenal syndrome – Prostacyclin, nitric oxide, glucagon – Splanchnic arterial vasodilation – Reduced effective blood volume – Activation of renin-angiotensin-aldosterone system and sympathetic stimulation – INTENSE RENAL VASOCONSTRICTION 76 CIRRHOSIS STOELTING 77 CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Acute Renal Failure Acute Tubular Necrosis – The liver’s role as a blood reservoir is impaired with cirrhosis so even modest blood loss can produce severe hypotension and lead to acute injury to the kidneys and other organs. – In patients with obstructive jaundice and elevated levels of conjugated bilirubin, this may contribute to renal tubule toxicity. 78 CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Coagulation Disorders – Clotting factors and vitamin K – Thrombocytopenia Present in > 50% of patients with advanced chronic liver disease Spontaneous bleeding is uncommon Causes of thrombocytopenia: – Portal hypertension-induced splenomegaly with sequestration of up to 90% of circulating platelets in spleen. – Increased destruction by immune mechanisms – Low-grade DIC – Sepsis – Bone marrow suppression by ethanol, folate deficiency 79 CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Endocrine Disorders – Abnormalities of glucose utilization Hypoglycemia – Inadequate glycogen stores and impaired gluconeogenesis – Impaired conversion of lactate to glucose Gonadal dysfunction – Males » Feminization, gynecomastia, shrinkage of testes and prostate – Females » Oligomenorrhea. amenorrhea 80 CIRRHOSIS – ORGAN SYSTEM DYSFUNCTION Hepatic Encephalopathy – Reversible, metabolic encephalopathy Ranging from minimal personality changes or sleep disturbances to confusion, lethargy, coma. 30 – 60% of cirrhotics have some HE – Precipitators of HE Large dietary protein load GI bleed Constipation Diuretics Azotemia Surgery and anesthesia 81 HEPATIC ENCEPHALOPATHY Most important factor is increased ammonia Global depression of CNS function – Possible mechanisms Increased availability of agonist ligands of GABA receptors, so-called natural benzodiazipines. – See improvement in mental status with flumazenil Disruption of blood-brain barrier Neurotoxic compounds Impaired cerebral energy metabolism 82 HEPATIC ENCEPHOLAPATHY Treatment – Prevention – Lactulose Not broken down in intestine Produces movement of ammonia from blood to bowel Cathartic – Neomycin Reduces urease-producing bacteria in gut – Zinc Two enzymes needed for conversion of ammonia to urea are zinc dependent – Liver transplant Survival without transplant – 1 year = 42% – 3 year = 23% BARASH 83 LESS COMMON CAUSES OF CIRRHOSIS Wilson’s Disease – Accumulation of copper in liver, etc Hereditary hemochromatosis – Excessive Fe++ absorption from bowel with subsequent tissue deposition Primary biliary cirrhosis – Likely autoimmune in nature α-1-Antitrypsin deficiency – Accumulation of abnormal α-1-Antitrypsin protein in liver Budd-Chiari – Outflow obstruction of hepatic veins 84 Figure 19-7 Schematic of pathways for cirrhosis-induced portal hypertension: the forward and backward theories. Cirrhosis and portal hypertension induce circulatory changes that decrease the effective blood volume. This activates volume receptors and stimulates neurohumoral and intrarenal reflexes to decrease renal blood flow and to increase renal retention of sodium. PVBF, portal venous blood flow; HABF, hepatic arterial blood flow; THBF, total hepatic blood flow; A-V, arteriovenous; PG's, prostaglandins; ADH, antidiuretic hormone; ANF, atrial natriuretic factor; PAF, platelet activating factor. (Reprinted with permission from Mushlin PS, Gelman S: Anesthesia and the liver. In Barash PG, Cullen BF, Stoelting RK [eds]: Clinical Anesthesia, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2001, p. 1088.) MILLER 10 HEPATOCELLULAR CARCINOMA 3rd most frequent cause of death from cancer 2.4/100,000 in U.S. Usually follows cirrhosis Worldwide- large majority follow viral hepatitis United States – 30 – 40% after viral hepatitis Treatment: – Liver transplant – Few patients have a surgically resectable tumor at the time of presentation 86 PREGNANCY-RELATED LIVER DISEASE Typically presents 3rd trimester or immediately postpartum – Acute Fatty Liver of Pregnancy Rarely severe Most recover fully Treatment: Expedite delivery – HELLP Hemolysis Elevated Liver enzymes Low Platelets Treatment: Expedite delivery Severe coagulopathy is rare and should make you consider Acute Fatty Liver Disease as well. 87 CHOLESTATIC DISEASE Produces an increase in circulating bile salts – Disease pattern similar to cirrhosis but less severe: Peripheral vasodilation Increased cardiac output Increased portal venous pressure Decreased portal venous flow – Coagulopathy Primarily secondary to vitamin K deficiency 88 PERIOPERATIVE MANAGEMENT PREOPERATIVE ASSESSMENT PREOPERATIVE RISK ASSESSMENT PERIOPERATIVE MANAGEMENT POSTOPERATIVE LIVER DYSFUNCTION 89 PREOPERATIVE ASSESSMENT History – Chronic hepatic disease or biliary obstruction – Acute liver failure: Nausea/ malaise rapid onset of jaundice altered mental status Exam – Icterus, jaundice, ascites, spider angiomata, petechiae, asterixis, gynecomastia, splenomegaly, palpation of liver. 90 PREOPERATIVE LABORATORY ASSESSMENT No history or physical exam suggestive of liver disease: – No preop screening lab drawn Hepatic disease known or suspected – Draw lab to quantify degree of dysfunction Abnormal lab (LFTs) in the absence of history or physical exam findings: – Safest approach is delay of surgery to avoid catching someone in the early, undiagnosed stages of liver disease – Not always practical 91 PREOPERATIVE ASSESSMENT OF ABNORMAL LIVER FUNCTION TESTS MILLER 92 PERIOPERATIVE RISK ASSESSMENT Acute hepatic disease, regardless of the etiology, increases perioperative morbidity and mortality. If patient is known to have acute hepatic disease, elective surgery should be postponed. The worse the liver dysfunction, the greater the increase in morbidity and mortality. So important to quantify. 93 PREDICTION OF RISK STOELTING 94 HEPATIC RISK FACTORS vs. COMPLICATIONS RISK FACTORS – Child-Pugh factors – Ascites – Cirhosis Other than primary biliary – – – – – – – Serum creatinine COPD Preop infection Preop upper GI bleed Higher ASA physical status Intraop hypotension Higher surgical severity score MILLER 95 PERIOPERATIVE RISK ASSESSMENT CHILD (1964) Serum Albumin Serum Bilirubin Ascites Encephalopathy Nutritional status CHILD – PUGH (1972) Serum Albumin Serum Bilirubin Ascites Encephalopathy PT 96 CHILD-PUGH SCORE 97 PREOPERATIVE EVALUATION OF PATIENT WITH LIVER DISEASE 98 PREOPERATIVE RISK ASSESSMENT CHILD – PUGH SCORE SURGICAL MORTALITY HOSPITALIZATION MORTALITY A 10% 4% B 30% 14% C 82% 51% ADAPTED FROM BARASH MELD SCORE MELD score = 0.957 x loge (creatinine mg/dl) + 0.378 x loge (bilirubin mg/dl) + 1.120 x loge (INR) + 0.643 Now used in the United States in prioritization for liver transplant. 99 PREOPERATIVE CONCERNS Extent of liver disease Age Coexisting disease Type, location, duration of surgery – GI and Emergency surgeries associated with the highest risk of death Optimize what you can: – – – – – – Coagulopathy Nutrition status Anemia Spontaneous bacterial peritonitis (or other infection) Hepatic encephalopathy ETOH dependency 100 PREOPERATIVE MEDICATIONS Sedation – Increased cerebral uptake of benzodiazipines – Consider decreased doses – Careful titration Consider Aspiration Prophylaxis – H2 blocker – Metoclopramide – Sodium bicitrate 101 INDUCTION OF ANESTHESIA Thiopental ( ↓ HER) – Elimination T1/2 unchanged in cirrhosis Propofol (↑ HER) – Elimination profile unchanged from control – May see slight increase in recovery time following infusion Etomidate (↑ HER) – Clearance unchanged in cirrhosis – Increased Vd may result in prolonged elimination T1/2 and unpredictable recovery Ketamine (↑ HER) 102 OPIOIDS AND ADJUNCTS Morphine/ Demerol – 1.5 – 2 fold decrease in clearance and increase in elimination T1/2 Alfentanil – Pronounced and prolonged effects due to: Increased free fraction Decreased clearance Fentanyl – No change in volume of distribution – Increased Elimination T1/2 due to decreased clearance Sufentanil – No significant pharmacokinetic change from control – May have slightly prolonged effect following multiple doses Remifentanil – Clearance unaltered in severe liver disease Dexmedetomidine – Significantly decreased clearance and prolonged half-lives 103 BOTTOM LINE ON INDUCTION AGENTS Decreases in plasma proteins may result in an increase of free drug and more significant responses to a “standard” dose of these drugs. 104 MAINTENANCE OF ANESTHESIA Volatiles – Previously discussed Goals: – Avoid direct drug-related toxicity – Maintain adequate hepatic perfusion and oxygenation – How: Maintain adequate: – – – – Cardiac output Blood volume Perfusion pressure Oxygenation Prompt replacement of fluid and blood 105 MUSCLE RELAXANTS Succinylcholine – Decreased plasma cholinesterase – Likely not an issue Mivacurium – Plasma cholinesterase – Prolonged Atracurium/ Cisatracurium – Hofman elimination, so essentially independent of hepatic and renal disease Figure 55-4 Disappearance of vecuronium from plasma after a single bolus dose of 0.2 mg/kg. A semilogarithmic plot of plasma concentration versus time shows that the vecuronium concentration remained at a much higher level during the elimination phase in patients with cirrhosis (open circles) than in normal control patients (black circles). This difference reflects the markedly decreased plasma clearance of vecuronium, increased elimination half-life, and increased duration of neuromuscular blockade in patients with cirrhosis versus normal individuals. (From Lebrault C, Berger JL, D'Hollander AA, et al: Pharmacokinetics and pharmacodynamics of vecuronium (ORG NC 45) in patients with cirrhosis. Anesthesiology 62:601-605, 1985.) Other NDPMRs – – – – Increased Vd so increased initial dose? Anticipate prolonged blockade Markedly decreased clearance Titrate to effect MILLER 106 PRESSORS Increased concentration of vasodilatory substances such as glucagon, resulting in markedly reduced response to catecholamines. Therefore: May need increased doses of catecholamines or the addition of a non-adrenergic vasoconstrictor like vasopressin. 107 MONITORING/ VENOUS ACCESS Need for invasive monitoring depends on: – Severity of liver dysfunction and effect on other organ systems – Coexisting disease – Anticipated extent of surgery Large bore IV access is a must in anything but the most peripheral cases. Remember: – May encounter coagulopathy and excessive bleeding – Will not tolerate hypovolemia well 108 CHOICE OF ANESTHETIC TECHNIQUE Local with Sedation – Least invasive if appropriate – Allows titration of drugs Regional – Typically well tolerated with: Adequate fluid loading Absence of coagulopathy GETA – If RSI not required, titration of drugs is beneficial 109 FLUIDS/ BLOOD PRODUCTS Colloids vs. crystalloids – No documented differences Monitoring of filling pressures appropriate in severe disease or more extensive surgery Decreased ability to move blood to the central circulation FOLLOWING 10% BLOOD LOSS PULMONARY BLOOD FLOW SPLANCHNIC BLOOD FLOW d CONTROL 15% 15% BILIARY OBSTRUCTION 7% NO CHANGE 110 POSTOPERATIVE LIVER DYSFUNCTION Common, but rarely severe May see jaundice postop following reabsorption of surgical hematoma in the absence of liver insult – However, large increases in serum transaminases reflect extensive hepatocellular necrosis Fulminant Hepatic Failure = – Encephalopathy within 2 weeks of development of jaundice or within 8 weeks of initial manifestation of hepatic disease. 111 POSTOPERATIVE JAUNDICE 112 POSTOPERATIVE JAUNDICE 1/2500 healthy patients may have significant heaptic dysfunction in the postop period unrelated to surgery or anesthesia. Study of 7,260 ASA 1 surgery patient screened with LFTs preop – 11(1/700) found to have increases in AST, ALT, LDH and surgeries cancelled. – All 11 had overt hepatic disorders and 3 (1/2500) became clinically jaundiced. – None of the 7,609 patients receiving anesthesia developed abnormal LFTs or became jaundiced. Management of Postoperative Hepatic Dysfunction – D/C any suspect medication – Investigate potential sources of infection – Consider extrahepatic biliary obstruction – Lab studies to quantify 113 SOURCE MATERIAL MILLER’S ANESTHESIA – 9th edition. Miller CLINICAL ANESTHESIA – 8th edition. Barash, Cullen, Stoelting BASICS OF ANESTHESIA – 6th edition. Stoelting, Miller 114