69: Liver Transplantation

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CHAPTER 69 Liver Transplantation

Matthew J. Fiegel, MD

1 What is the Model for End-stage Liver Disease MELD?

The Model for End-stage Liver Disease (MELD) is a scoring system for prioritizing patients for liver transplantation. The MELD score is an objective model that predicts a patient’s 90-day mortality while waiting for a liver transplant. It is a better predictor of perioperative mortality than the Child’s scoring system and therefore has replaced it. MELD is calculated using bilirubin, international normalized ratio, and creatinine (the MELD calculator can be accessed at www.UNOS.org). There are four listing status categories for patients with liver disease:

Status 1 includes patients with acute liver failure/disease with an estimated survival of less than 7 days (highest priority for liver transplantation).

Status 2a (MELD score >29) includes patients with end-stage liver disease, severely ill, and potentially hospitalized.

Status 2b (MELD score 24–29) includes patients with end-stage liver disease, severely ill, but not requiring hospitalization.

Status 3 (MELD score <24) includes patients with liver disease that is too early for cadaveric transplantation but may be a suitable live donor transplantation candidate.

2 Describe some indications and contraindications for liver transplantation

Indications for liver transplantation include end-stage liver disease from hepatocellular disease, cholestatic disease, vascular disease, or polycystic disease. In addition, some nonresectable hepatic malignancies, metabolic liver diseases, and fulminant hepatic failure are indications (Table 69-1). Over time relative and absolute contraindications for liver transplantation have evolved (Table 69-2). Because MELD predicts 3-month survival, those with the highest scores have the greatest chance of dying from liver disease and thus have the best risk-benefit ratio for undergoing liver transplantation.

TABLE 69-1 Indications for Liver Transplantation

TABLE 69-2 Contraindications to Liver Transplantation

AIDS, Acquired immunodeficiency syndrome; HIV, human immunodeficiency virus.

Modified from Maddrey WC, Van Thiel DH: Liver transplantation: an overview, Hepatology 8:948, 1988.

3 How does the cardiovascular physiology of a patient with end-stage liver disease differ from that of a normal patient?

Patients with end-stage liver disease have a hyperdynamic circulation, characterized by increased cardiac index and decreased systemic vascular resistance. This results in a consistently lower blood pressure and increased heart rate. Patients are significantly less responsive to catecholamines. Cirrhotic patients tend to be overloaded with total body water but arterially dehydrated. Pulmonary blood flow is increased and can result in increased pulmonary artery pressures; pulmonary vascular resistance usually remains normal. Coronary artery disease with resulting impaired myocardial function (previously thought to be uncommon in patients with liver disease) may be present, especially when the patient has diabetes. Coronary artery disease in liver transplant patients older than 50 years occurs in a range of 5% to 27%. Abnormalities in both systolic and diastolic function may be present and result in an inadequate cardiac output for the degree of vasodilation. This is especially true in patients with a history of alcohol abuse.

4 What are some preanesthetic considerations in a liver transplant patient?

Optimal anesthetic management of these complex, critically ill patients requires management of the pathophysiologic changes of liver disease, comorbid conditions, and the physiologic changes associated with the surgery. In some instances (e.g., pulmonary hypertension, hepatorenal syndrome), hepatic disease may be overshadowed by the severity of the comorbid conditions. Prior abdominal surgeries and encephalopathy are important features to note, as are coagulation deficits (factor deficiencies and thrombocytopenia). The thromboelastogram (TEG) provides valuable insight into the patient’s entire clotting process. The TEG graphs the viscoelastic properties of a clot from the formation of the first fibrin strands to the full hemostatic plug. Thus the TEG is a dynamic test showing the evolution of clot formation. Because the TEG examines multiple phases of clot formation within a single test, it reflects information that is otherwise available only in multiple tests. The TEG is the best laboratory assessment of qualitative platelet function.

Electrolyte abnormalities are common. Hypokalemia is commonly seen in earlier stages of liver disease since hepatic injury leads to hyperaldosteronism. Hyperkalemia may be caused by the use of potassium-sparing diuretics to treat ascites and hepatorenal syndrome. Hyponatremia may result from diuretic use, hyperaldosteronism, or volume overload. Renal dysfunction should be assessed since intraoperative dialysis may be necessary. In fulminant hepatic failure, cerebral cytotoxic edema is a common complication, and there must be aggressive preoperative control of intracranial pressure to prevent brainstem herniation, a common cause of death. Patients with cerebral edema should have an intracranial pressure monitoring device.

Pulmonary hypertension associated with cirrhosis occurs in approximately 8% of patients and is a cause of significant intraoperative morbidity and mortality. Many liver failure patients are hypoxemic secondary to atelectasis and hepatopulmonary syndrome. All potential transplant candidates should undergo a screening transthoracic echocardiogram to assess pulmonary arterial pressures, left ventricular function, and intrapulmonary shunting. If pulmonary arterial pressures are elevated or right ventricular function is decreased, a right heart catheterization may be indicated.

5 What is the significance of portal pulmonary hypertension? How are these patients managed in the pretransplant period?

In contrast to most transplant recipients, portal pulmonary hypertension (PPHTN) patients have an increased risk of death because of right ventricular failure in the peritransplantation period. Physicians are uncertain which PPHTN patients may undergo transplantation because there are no patient characteristics that clearly predict outcome. Patients with moderate to severe PPHTN should not be considered candidates until they undergo a trial of vasodilator therapy. The cause of pulmonary hypertension in liver failure patients is unknown, but the disease shares many similarities with primary pulmonary hypertension. Tissue hypoxia likely plays a role. The pulmonary circulation has increased vascular resistance that is transmitted back to the right heart and liver. The pulmonary vessels of patients with PPHTN are unable to accommodate increased blood flow during periods of aggressive blood transfusion and during the hyperdynamic postreperfusion phase, potentially resulting in acute right ventricular failure. Rapid dilation of the right ventricle can also compress the right coronary vessels, producing myocardial ischemia and infarction. Pulmonary hypertension will not resolve in all patients who were successfully transplanted with a new liver.

Vasodilators reduce pulmonary artery pressures and prolong survival in some pulmonary hypertension patients. The prostaglandin epoprostenol (Flolan) can reduce pulmonary artery pressures when given as a chronic infusion and has been used to bridge patients to transplantation. Nitric oxide inhaled in doses up to 80 ppm also acutely reduces pulmonary artery pressures in a small number of PPHTN patients and has been used in the operating room to reduce pulmonary artery pressures. More recently, sildenafil (Revatio) has been implemented as an oral agent to reduce pulmonary hypertension in transplant candidates.

6 What are the concerns before anesthetic induction in the patient with end-stage liver disease?

The room should be prewarmed because hypothermia will only worsen the preexisting coagulopathy.

Preoxygenation should begin immediately on entering the operating room because hypoxemia is common in liver disease.

Ascites, active gastrointestinal bleeding, gastroesophageal incompetency because of prior sclerotherapy, or hepatic encephalopathy may result in delayed gastric emptying. Therefore these patients are at risk for pulmonary aspiration, and a rapid-sequence induction is indicated.

Plasma pseudocholinesterase levels are typically lower in this patient population, but a significant prolongation of the relaxant effect of succinylcholine is not common.

Because of the risk of variceal bleeding and presence of coagulopathy, a naso/orogastric tube should be placed very carefully. Transesophageal echo is relatively contraindicated for the previous reasons.

Liver disease affects drug distribution and metabolism. Patients with liver disease commonly have an increased volume of distribution, necessitating an increase in initial dose requirements. However, because the drug metabolism may be reduced, smaller doses are subsequently administered at longer intervals. The muscle relaxant cisatracurium has organ independent breakdown and thus is the preferred muscle relaxant for liver transplantation.

Fentanyl, although completely metabolized by the liver, does not show a prolonged effect in cirrhosis. It also does not decrease hepatic blood or oxygen supply. Either fentanyl or remifentanil are the opioids of choice during liver transplantation.

7 Describe the three stages of liver transplantation

The preanhepatic (dissection) stage (stage 1) begins with the surgical incision and dissection and mobilization of the patient’s diseased liver. During this stage the surgeons identify the hepatic artery, portal vein, and the inferior vena cava, above and below the liver.

The anhepatic stage (stage 2) isolates the liver from the circulation and commences with the occlusion of the hepatic artery and portal vein. Occlusion of the inferior vena cava above and below the liver is typically performed so the liver can be removed. During the anhepatic stage, the donated liver is reinserted into the circulation by anastomoses to the patient’s vena cava, portal vein, and hepatic artery. The anhepatic stage concludes with removal of the vascular clamps, resulting in reperfusion of the donor liver graft.

The reperfusion stage (stage 3) starts during portal vein reperfusion and extends to the conclusion of the operation. Biliary reconstruction takes place during this phase as does assessment of neohepatic function.

8 What is the role of venovenous bypass? Are there any alternatives?

During the anhepatic phase, after vascular clamps are placed on the inferior vena cava, venous return to the heart drops precipitously. To improve blood return, some physicians use a bypass circuit to return venous blood from the lower part of the body back to the thorax. However, some physicians control the decline in blood pressure that occurs during occlusion of the vena cava with vasopressors rather than with venovenous bypass. Another alternative is to place a cross-clamp over part of the vena cava and remove the liver with the part of the vena cava attached to the hepatic veins. Because part of the vena cava remains open to flow, venous return from the lower body is not compromised. Choice of technique depends on the amount of scarring surrounding the liver and surgeon preference.

9 List some of the anesthetic concerns during the preanhepatic (dissection) phase

Instituting warming measures early and maintaining normothermia are important because the metabolic activity of the liver contributes significantly to maintaining body temperature. Early temperature losses during the procedure are difficult to correct and potentiate coagulation disturbances.

Hyperkalemia resulting from administration of blood products and impaired excretion caused by hepatorenal syndrome can be a life-threatening complication leading to cardiac arrest. The donor organ preservative solution contains 150 mEq/dl of potassium. On reperfusion, much of this potassium reaches the patient’s circulation. Therefore it is important to control potassium early in the surgery, maintaining serum levels at approximately 3.5 mEq/dl. This is achieved with loop diuretics (furosemide) and hyperventilation. If these agents fail, intraoperative hemodialysis should be considered.

Hyponatremia in patients with liver disease should not be corrected rapidly because fluctuations in the serum sodium during transplantation have produced pontine demyelination, resulting in debilitating disease or death.

Because citrate in banked blood normally undergoes hepatic metabolism, it accumulates during liver transplantation. Citrate binds calcium and can contribute to profound hypocalcemia.

Blood loss during this stage can be significant. It should be anticipated in any patient who has had previous intra-abdominal surgery, especially in the right upper quadrant.

Besides preexisting coagulopathies, mechanical reasons for excessive bleeding in liver failure patients include increased portal pressures with excessive splanchnic venous filling and hyperdynamic flow.

Patients with cirrhosis have splanchnic hypervolemia. Often splanchnic vasoconstrictors such as vasopressin are started in an attempt to return the splanchnic blood to the arterial circulation.

By the completion of this phase, patients should be warm, have coagulopathies and intravascular deficits corrected, display good urine output, and possess normal electrolytes.

10 What are some anesthetic concerns that arise during stage 2, the anhepatic phase?

Once the dissection is finished, blood loss is usually minimal, but blood volume may be decreased from hemorrhage during the preanhepatic phase. Because the inferior vena cava is typically cross-clamped, half of the patient’s blood volume is confined to the lower body. Therefore central filling pressures are a poor representation of total body blood volume. Most therapy in this phase is directed toward achieving hemodynamic stability and preparing for reperfusion by correcting potassium and pH. Steroids are also administered during this stage. Steroids are the initial step in rendering the patient immunosuppressed so he or she will not reject the new organ. They must be administered before reperfusion.

Hyperkalemia, hypocalcemia, and metabolic acidosis are common during the anhepatic stage and must be corrected since the anhepatic patient has no means of physiologic compensation. Hypernatremia caused by administration of sodium bicarbonate for metabolic acidosis is managed by administration of dextrose in water (D₅W). Increases in PaCO₂ associated with bicarbonate administration also require adjustments in ventilation. Perhaps a better buffering agent is tromethamine (THAM). THAM is a low sodium buffer that does not increase sodium or PaCO₂. As previously discussed, serum potassium must be aggressively lowered to <3.5 mEq/L to prevent hyperkalemia-induced asystole during reperfusion. Hyperventilation, alkalinizing agents, and insulin are all effective at doing this. The severity of these electrolyte abnormalities is related to the length of stage 2, severity of patient illness, hypotension, number of blood products administered, and renal function.

An acute decrease in venous return following caval occlusion leads to hypotension. There is relative hyperemia inferior to the cross-clamp and poor venous return above the cross-clamp. Distal anatomic shunts may act as capacitance vessels, sequestering intravascular volume and regulating rates of venous return. New vessel formation, in addition to enlargement of portosystemic connections, will influence central venous return and therefore cardiac output following caval occlusion. Although there are no reliable predictors of hemodynamic instability during venous occlusion, an accentuated hyperdynamic circulatory state, severe portal hypertension, and advanced age have been associated with adverse hemodynamic events.

11 Define reperfusion syndrome. What are its clinical implications?

Reperfusion syndrome is characterized by either a decrease of 30% or more in mean arterial pressure (from baseline) for greater than 1 minute and occurring within the first 5 minutes of reperfusion or a mean arterial pressure less than 60 mm Hg under the same circumstances. Following portal vein unclamping, approximately 30% of patients will exhibit profound cardiovascular collapse on reperfusion irrespective of attentive management during stage 2. This tends to be more profound with a histidine, tryptophan, ketoglutarate preservative solution as opposed to a University of Wisconsin preservative solution. The bradycardia, myocardial depression, and systemic vasodilation noted during reperfusion are secondary to rapid increases in serum potassium, decreases in temperature, acute acidosis, and release of vasoactive substances by the grafted liver. These vasoactive mediators include prostaglandins, kallikrein, platelet-activating factor, and leukotrienes. Increased age and larger donor organs also are considered risk factors.

Generally treatment with calcium, atropine, and/or epinephrine improves cardiovascular function. Fluid administration should be judicious because it can aggravate the already increased filling pressures (secondary to myocardial depression), resulting in impaired hepatic perfusion. Although the hemodynamic changes generally subside within 10 to 15 minutes, pulmonary hypertension, elevated central venous pressure, and hypotension may persist. Continuous vasopressors such as vasopressin or phenylephrine may be necessary to combat the persistent vasodilation.

12 Describe some of the major anesthetic management issues during the reperfusion stage (stage 3)

Wide swings in blood pressure and arrhythmias can be expected. Hypertension may be caused by a large increase in blood flow from the lower body to the systemic circulation following unclamping of the inferior vena cava. Alternatively release of the portal vein clamp directs blood through the liver graft to the heart, and products of cell death and residual preservation fluid can cause severe hypotension, bradycardia, supraventricular and ventricular arrhythmias, electromechanical dissociation, and occasionally cardiac arrest. Many of these complications can be attenuated by meticulous management during stage 2.

Hypotension may also be the result of surgical bleeding since the anastomotic sites are exposed to venous pressure.

Mild to severe coagulation defects are commonly observed during stage 3 because the new liver requires time to resume its synthetic functions. Treatment should be guided by the TEG. Clotting variables gradually return to normal by a combination of specific replacement therapy and production by the allograft. Fibrinogen levels should be assessed in the setting of ongoing bleeding and lack of clot formation.

Urine output typically improves, even in patients with prior hepatorenal syndrome, and inotrope requirements diminish.

The procedure is completed by biliary reconstruction, either by direct bile duct-to-duct anastomosis or by a Roux-en-Y choledochojejunostomy.

KEY POINTS: Liver Transplantation

1. The anesthesiologist should be a member of the hospital liver transplant team and play a critical role in the pretransplant evaluation and candidate selection process.

2. Although patients with end-stage liver disease have a hyperdynamic circulation characterized by increased cardiac index and decreased systemic vascular resistance, impaired myocardial function, coronary artery disease, and pulmonary hypertension are common.

3. Patients with liver disease commonly have an increased volume of distribution, necessitating an increase in initial dose requirements. However, because the drug metabolism may be reduced, smaller doses are subsequently administered at longer intervals.

4. Concerns during the preanhepatic stage of liver transplantation include aggressive rewarming; attention to serum potassium, sodium, and calcium levels; replacing significant blood losses; treating coagulation disturbances; and restoring effective arterial blood volume.

5. Concerns during the anhepatic stage include correction of hyperkalemia, hypocalcemia, and metabolic acidosis and restoration of intravascular volume in anticipation of vascular unclamping and reperfusion syndrome.

6. Wide swings in blood pressure and arrhythmias can be expected during the postanhepatic stage. Surgical bleeding and impaired coagulation are concerns. Urine output typically improves, the biliary tree is reconstructed, and graft function must be assessed.

SUGGESTED READINGS

1. Baker J., Yost S., Niemann C. Organ transplantation. In: Miller R.D., editor. Anesthesia. ed 6. Philadelphia: Churchill Livingstone; 2005:2231-2283.

2. Csete M., Glas K. Anesthesia for organ transplantation. In: Barash P., editor. Clinical anesthesia. ed 5. Philadelphia: Lippincott William & Wilkins; 2006:1364-1367.

3. Krenn C., De Wolf A. Current approach to intraoperative monitoring in liver transplantation. Curr Opin Organ Transplant. 2008;13(3):285-290.

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