OVERVIEW OF LIVER FUNCTION
The liver plays a wide variety of roles in the overall scheme of the normal physiology of the body. The liver is involved in many aspects of metabolism, such as (1) lipid metabolism through fatty acid synthesis and lipoprotein conversion and (2) carbohydrate metabolism via glycogen storage, release. It is also the site of gluconeogenesis and amino acid metabolism. The liver is involved in synthesis of important proteins such as albumin and some of the coagulation factors. It also plays a role in immune system response, filtering out toxins and bacteria from the gastrointestinal tract, as well as amplifying the immune response via immune cells present in the liver. In addition, the liver is involved in endocrine control, via synthesis and secretion of hormones such as insulin-like growth factor 1 and angiotensinogen, as well as through inactivation of hormones such as insulin and corticosteroids. The liver also plays a major role in the coagulation system via synthesis of proclotting and anticlotting factors. Finally, it functions in modulating blood volume, acting as a reservoir for blood volume that can then be released into the bloodstream when stimulated by the sympathetic nervous system.1
CIRRHOSIS OF THE LIVER
Because of the liver’s central role in normal physiology, when the liver fails, there are wide-ranging effects on other organ systems. The degree of secondary involvement can alter dosing strategies and also influences the approach to certain parts of anesthetic use. Notable organs or organ systems at risk for secondary impairment due to liver failure are the cardiovascular system, brain, lungs, kidneys, gastrointestinal system, endocrine, immune system, and bone marrow. Liver transplant is the only definitive treatment for end-stage liver disease.2,3
The cardiovascular manifestations are arteriolar vasodilation and increased cardiac output, characterized as a hyperdynamic state due to decreased metabolism of vasoactive substances. Brain manifestations are the result of accumulation of toxic metabolites and can lead to hepatic encephalopathy and increased intracranial pressure. Possible pulmonary manifestations are restrictive lung disease, intrapulmonary shunts, pulmonary hypertension, and ventilation–perfusion mismatch, and hypoxemia in the absence of ascites or intrinsic lung disease (hepatopulmonary syndrome). The kidneys can fail in patients with end-stage renal disease without a primary cause of renal disease, known as hepatorenal syndrome. Common gastrointestinal manifestations are ascites, esophageal varices, portal hypertension, and delayed gastric emptying. Hematologic effects are anemia due to malnutrition, chronic disease, or bleeding, and coagulopathy due to platelet defects (number of platelets, function of platelets, or both), decreased number of clotting factors, decreased clearance of activated factors, and hyperfibrinolysis.3
The Child-Turcotte-Pugh (CTP) scoring system is commonly used to grade the severity of liver disease and life expectancy at 1 and 2 years. The CTP classification includes 5 factors: ascites, level of encephalopathy, prothrombin time, plasma bilirubin level, and serum albumin level (Pugh’s modification of the original scoring system replaced nutritional status with prothrombin time). The severity of each variable is assessed, and based on the total score patients are placed into class A (minimal), B (moderate), or C (advanced) disease.2,4 Although the CTP class offers an assessment of severity of liver disease, it offers only minimal guidance on how to adjust drug dosing in liver disease because it does not address the specific ability of the liver to metabolize individual drugs.5
CTP was initially used in allocation of organs for transplant but has been supplanted by the model for end-stage liver disease (MELD) score. The MELD score offers an estimate of 3-month mortality, making it more useful in identifying liver transplant recipients. The MELD score is calculated from serum creatinine and bilirubin concentrations and the international normalized ratio (INR). The higher the MELD score, the more severe the underlying liver disease.4 MELD scores less than 20 indicate a low 30-day mortality (less than 6%). MELD scores above 20, 30, and 40 indicate approximately a 20%, 50%, and 70% 30-day mortality, respectively. Like the CTP score, the MELD score offers minimal guidance on how to adjust an anesthetic for patients with liver disease.
HEPATIC DRUG CLEARANCE
Decreased liver function can substantially alter the behavior of several anesthetic drugs. Changes may be due to alteration in drug pharmacokinetics, drug pharmacodynamics, or both. How these changes affect the onset and duration of effect for anesthetic drugs is not well defined but worth considering when formulating a dosing regimen in patients undergoing a liver transplant.6 In general, anesthetics metabolized by the liver can have a prolonged effect, especially if administered as a continuous infusion, and will require lower infusion rates. For bolus-dose administration, careful titration is recommended to achieve anesthetic goals of unresponsiveness, analgesia, and muscle relaxation. In otherwise healthy individuals, conventional dosing schemes are often adequate. Unfortunately, guidelines that indicate how doses should be adjusted in the setting of liver failure based on liver function scores do not exist.
For drugs that are metabolized by the liver, clearance is a function of liver blood flow and intrinsic clearance. These processes are quantified using the hepatic extraction ratio, defined as the rate of drug removal divided by the rate of drug delivery to the liver.
Intrinsic clearance refers to the ability of the liver to extract a drug independent of blood flow or protein binding. Each drug has its own intrinsic clearance; it can be low, intermediate, or high. Drugs with a low intrinsic clearance typically have a low extraction ratio (ie, the rate of drug’s entering and exiting the liver are nearly the same). Drugs with a high intrinsic clearance typically have a high extraction ratio (ie, the rate of drug’s leaving the liver is much lower than the rate of drug’s entering the liver). Doubling the intrinsic clearance of a drug with a low intrinsic clearance will lead to an almost proportional change in extraction and thus clearance. However, if a drug has a high intrinsic clearance, doubling the intrinsic clearance will have little effect on drug clearance or extraction ratio.6
The effect of hepatic blood flow changes on the extraction ratio is also dependent on intrinsic clearance. In general, the extraction ratio is inversely proportional to hepatic blood flow. Decreasing hepatic blood flow leads to a relatively small increase in the extraction ratio for drugs with a high intrinsic clearance and a larger increase in the extraction ratio for drugs with a low intrinsic clearance. The effects of changes in flow on hepatic clearance are compensated by an opposing trend in extraction for drugs with small intrinsic clearance values, and their clearance is essentially independent of blood flow. If a drug has a high intrinsic clearance and extraction, hepatic clearance is essentially determined by the delivery of drug to the liver, and changes in the hepatic blood flow will lead to proportional changes in clearance.6
THE EFFECT OF LIVER FAILURE ON PHARMACOKINETICS AND PHARMACODYNAMICS
The liver plays a central role in drug metabolism. Hepatic dysfunction affects drug pharmacokinetics by a variety of possible mechanisms. One mechanism is reduced oxidation and reduction of anesthetic drugs via hepatocyte microsomal enzymes in damaged liver tissue. A second mechanism is reduced biliary excretion. Conjugated drugs are delivered via biliary excretion back to the gastrointestinal tract for reabsorption, eventually leading to reduced renal excretion. A third mechanism is a function of liver production of plasma proteins. A reduction in plasma proteins can increase the free fraction of drug, allowing more of it to be eliminated (ie, some drugs may pass through the glomerular apparatus when unbound to protein but remain in the blood when bound). Portosystemic shunting, which occurs in varying degrees depending on the blood pressure required to perfuse a diseased liver, will decrease the presystemic elimination of orally administered drugs (ie, the first-pass effect), leading to an increase in bioavailability.1,5
Metabolic pathways are differentially affected in liver dysfunction. In early cirrhosis, drug glucuronidation is spared relative to oxidative metabolism. In advanced cirrhosis, drug glucuronidation may also be substantially impaired. Liver dysfunction can also affect the clearance of drugs or active metabolites that are normally cleared by the kidney. Even moderate degrees of hepatic impairment lead to a decrease in clearance of drugs normally cleared by the kidney.7 Table 33–1 lists common drugs in anesthesia that undergo oxidative metabolism via the cytochrome enzyme system; as liver function worsens, it may be necessary to consider lowering the dose of these drugs.8
There are a couple of potentially important pharmacodynamic alterations in patients with cirrhosis. One, with rising plasma ammonia levels and brain swelling, there can be an increased sensitivity to sedative drugs. Two, there may also be a decrease in sensitivity to catecholamines and other vasoconstrictors.1
LIVER TRANSPLANTATION SURGERY
The goal of a liver transplant surgery is to remove the diseased native organ and replace it with a functioning liver. There are many factors that affect graft function, such as the ischemia time (warm and cold), steatosis of the donor liver, and age of the donor. Assuming an uneventful transplant, the donor liver should begin functioning prior to the end of the surgery. Signs of liver graft function are bile production, correction of coagulopathy without transfusion directed at correcting it, decreasing lactate level, and a rise in core temperature.3,9
There are 3 main phases to a liver transplant surgery: preanhepatic, anhepatic, and reperfusion. Each phase has unique challenges. Communication between surgical and anesthesia teams is critical because the surgical technique, particularly during the preanhepatic phase, will influence anesthetic management.