Giuditta Angelini
Zoltan G. Hevesi
Douglas B. Coursin
Liver failure or end-stage liver disease (ESLD) is the fourth leading cause of death in the United States in patients 45 to 54 years of age and 12th among all age groups (1). Liver transplantation is the only definitive cure for irreversible liver failure. The etiology of liver failure is well reviewed elsewhere in this textbook. The first several liver transplants performed in the 1960s and 1970s resulted in a 75% mortality within 1 year (2). The intervention that improved survival dramatically was the clinical introduction of cyclosporine in the late 1970s. Since then, many innovations have further improved the prognosis after liver transplantation. Depending on the degree of liver failure, survival is now 73% to 81% at 1 year (3). Several developments have occurred during the intervening time period due to an improved understanding of the physiology of liver failure and management during the perioperative period. Currently in the United States, there are 127 liver transplant centers (4) and about 17,000 patients on the liver transplant waiting list (5). It is important for intensive care unit physicians to understand the process of liver transplantation including preoperative assessment, intraoperative management, and postoperative priorities to optimize their ability to positively affect the outcome of these often complex patients.
Key Points
1. The model for end-stage liver disease (MELD) is a system recently developed and extensively studied to accurately predict short- and intermediate-term mortality. It is based on the parameters of bilirubin, international standardized ratio, and creatinine. It is the new method on which allocation of transplant organs is based.
2. Patients with liver failure can have alterations in their cardiovascular, pulmonary, and renal physiology that can impact their prognosis after liver transplantation.
3. Blood product use during the management of the liver transplant patient should be judicious despite significant coagulation defects. This will also help to avoid hypervolemia, as both of these can significantly impact prognosis after liver transplantation.
4. Patients undergoing liver transplantation need constant surveillance of their fluid and electrolyte status to avoid complications.
5. Although most patients will experience a mild increase in aminotransferases after transplantation, there are several complications that can significantly increase the degree or duration of this rise and require evaluation.
Presurgical Process
The appropriate assignment and prioritization of scarce resources such as solid organs remains a challenge with organizations such as the United Network of Organ Sharing (UNOS), which strives to achieve optimal and fair distribution for transplantation. Since 2001, the MELD scoring system has been the accepted method of prioritizing liver allocation for an individual patient (6). It is calculated as shown in Table 93.1 using logarithmic numbers of the following serum indices: bilirubin, international standardized ratio (INR) for prothrombin time, and creatinine. Any patient who is on dialysis receives an automatic 4 mg/dL for his or her creatinine score. The only exception to the MELD scoring system for listing transplant candidates are status 1 patients who have acute fulminant liver failure (6). Initial research on the MELD score included a fourth number reflecting the cause of liver failure, which is no longer used. However, it is replaced by adding 0.643 for all patients to make the literature comparable despite the change. A calculator for the MELD score can be found at the UNOS Web site (www.unos.org/resources/meldPeldCalculator.asp).
The MELD score has been shown to be a better predictor of short- and intermediate-term morbidity and mortality among patients with liver failure than the previously used Child-Pugh Score (7,8) as well as other less well known scoring systems. In addition, once the score rises above 21, it also outperforms composite indicators such as persistent ascites or encephalopathy. There is a subset of patients at higher risk for mortality than calculated by the MELD score; the increased mortality is based on persistent ascites and hyponatremia, factors likely related to the potential for developing renal failure (9).
Patients with hepatocellular cancer (HCC) can have an excellent prognosis if liver transplantation occurs early, but their disease progression is not well represented by MELD. Therefore, the HCC patients are assigned a MELD score based on their stage according to the Milan criteria, which evaluate the number and size of liver tumors present on a CT scan or MRI. This “MELD exception” score attempts to predict the chance of progression to inoperability within 90 days. Periodically, the system is adjusted to make the allocation fair for all patients with ESLD as well as HCC. UNOS continuously monitors waiting list dropout and reviews patient scores to maintain impartiality (10). Other patients may be considered on a case-by-case basis for exception as published by the MELD exception study group (11). Potential candidates include those suffering from hepatopulmonary syndrome, primary hyperoxaluria, familial amyloid polyneuropathy, cystic fibrosis, and small-for-size syndrome.
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Table 93.1 Model for End-stage Liver Disease |
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Cardiovascular Issues
The cardiac physiology of liver failure is characterized as a hyperdynamic profile with a high cardiac output. If there is any degree of dysfunction, it has been assumed in the past that the patient suffered from alcohol chronic toxicity, which is responsible for 30% of dilated cardiomyopathies (12). However, it is becoming evident that a significant amount of systolic dysfunction and even more diastolic dysfunction is present in patients with ESLD of all causes including nonalcoholic (13). In addition, the potential for coronary artery disease has been underappreciated previously in the potential liver transplant patient. Current studies suggest that the prevalence of coronary artery disease in patients with ESLD is at least as common and probably more so than in the general population. Patients may also be less symptomatic despite moderate to severe coronary heart disease (14). At least 50% of patients with coronary artery disease will suffer significant morbidity and mortality while undergoing a liver transplantation (1).
Patients with liver failure demonstrate blunted cardiac response to stimuli such as hemorrhage, hypovolemia, and administration of inotropic drugs (15). In ESLD patients, there are several elevated levels of circulating vasodilators such as nitric oxide, tumor necrosis factor-alpha (TNF-α), and prostaglandins, so patients are often autotreated for cardiac failure by their evolving pathophysiology (13). However, when challenged with a dramatic increase in preload from shunted mesenteric venous blood, as occurs in the transjugular intrahepatic portosystemic shunt (TIPS) procedure, cirrhotic patients have a 12% risk of heart failure (16). The risk of mortality secondary to heart failure from liver transplantation is at least 7% (17).
The prevalence of cirrhotic cardiomyopathy is difficult to assess since no firm diagnostic criteria exist, and its presence only becomes evident under stress. The prognosis correlates with the degree of liver failure and does improve over time after transplantation. The presence of cirrhotic cardiomyopathy can potentiate the occurrence of hepatorenal syndrome (13). β-Adrenergic receptor desensitization occurs so the normal inotropic and chronotropic responses to isoproterenol and dobutamine are attenuated (18,19).
The high pressure present in the hepatic sinusoids and hypoalbuminemia associated with ESLD increases Starling forces in the direction to translocate fluid to the abdominal cavity, which results in total body volume overload secondary to resultant ascites but with intravascular depletion (20). Adding the vasodilatory state associated with liver failure results in decreased end organ perfusion and predisposes to complications such as the hepatorenal syndrome discussed below. Every attempt to maintain intravascular repletion and euvolemia should be exercised. At least part of fluid resuscitation in ESLD patients should include albumin, as it has been shown to improve patient survival after the onset of ascites in long-term management of liver failure (21).
Pulmonary Disorders in Liver Failure
There are several reasons for pulmonary disease to develop in patients with liver failure. Some are related to the cause of liver failure such as emphysema with alpha-1 antitrypsin deficiency and fibrosing alveolitis associated with primary biliary cirrhosis. Additionally, complications of portal hypertension can affect lung function due to overwhelming ascites, which can decrease functional residual capacity and cause hepatic hydrothorax. However, the pulmonary issues that receive the most attention include the vascular abnormalities of hepatopulmonary syndrome and portopulmonary hypertension (22).
Approximately 40% of cirrhotic patients have hepatopulmonary syndrome, with approximately 8% to 15% developing impaired oxygenation. Essentially, the patient develops pulmonary arteriovenous dilations due to the increased presence of vasodilators. The gold standard in diagnosis is a contrast echocardiogram demonstrating intrapulmonary shunting. There is no effective treatment for this disease, but transplantation results in an 85% resolution or significant improvement (22). The duration of time until that improvement occurs can be quite variable, anywhere between a few days to 14 months postoperatively. Unfortunately, there are no good indicators to predict reversibility (23). Baseline room air arterial oxygenation of ≤50 mm Hg has been shown to worsen survival despite liver transplantation (24).
Conversely, portopulmonary hypertension is essentially pulmonary hypertension, which occurs in 2% to 5% of cirrhotic patients (25). It does not correlate with the degree of portal hypertension or liver failure. Using a cutoff of 40 mm Hg for right ventricular systolic pressure, the sensitivity of echocardiogram is 80% and the specificity is 96% (26).
The treatment of portopulmonary hypertension is not at all the same as for other types of pulmonary artery hypertension (PAH). At the present time, diuretics and epoprostenol have been the best studied and the most likely to provide benefit. Recommended therapies for PAH such as anticoagulation, calcium channel blockers, beta blockers, and endothelin receptor antagonists can have adverse effects either on the prognosis of portopulmonary hypertension or on liver failure in general. TIPS is contraindicated in this setting. Sildenafil may have some benefit, but it does increase the production of endogenous nitric oxide and can further exacerbate systemic hypotension (25).
When the mean pulmonary artery pressure is >50 mm Hg, liver transplantation is contraindicated, as the mortality has been documented to be 100% (27). It is considered a contraindication due to the fact that transplantation will decrease the amount of circulating prostaglandins and result in worsening of the disease. Below a mean pulmonary artery pressure of 35 mm Hg, proceeding with liver transplantation can occur without delay. Between 35 and 50 mm Hg, optimizing the patient's status with diuretics and epoprostenol is indicated prior to liver transplantation (25).
Hepatorenal Syndrome
Hepatorenal syndrome (HRS) is a functional type of renal impairment that occurs in 11.4% of patients with liver failure within 5 years of the first episode of significant ascites (28). There are two types, which are both potentially reversible with liver transplantation. HRS 1 is rapidly progressive, with a doubling of initial creatinine to above 2.5 mg/dL or 50% reduction of creatinine clearance to less than 20 mL/minute, which occurs in less than 2 weeks. The mortality rate is nearly 100% within 10 weeks of development. HRS 2 is associated with a more moderate, steady decline in renal function (29). The 1-year probability of survival is 38.5% with HRS 2, but the mean survival of HRS 1 is only 7 ± 2 days (28). A more complete discussion of this topic is found in the chapter on liver failure. Therefore, the focus here will be regarding the goals of therapy during liver transplantation in patients with HRS.
The most successful management to prevent further injury during surgery is to alter the physiology that led to the development of HRS. The effect of peripheral and splanchnic vasodilation from cytokines and nitric oxide, as well as the intrarenal vasoconstriction that occurs in response to intravascular depletion are both aspects of liver failure that combine to produce this syndrome (29). Obviously, euvolemia is a primary goal, and in most studies looking at prevention and improvement of HRS, albumin is used as an adjuvant therapy.
Vasopressin analogues administered with albumin to patients with both types of HRS have been shown to improve glomerular filtration rate and creatinine levels (29). Pretransplant normalization of kidney function with terlipressin has been shown to provide similar outcomes after liver transplantation similar to patients with normal renal function (30). There is also a survival advantage while waiting for transplantation if terlipressin is administered, but only if the transplant occurs within 3 months. The major risk associated with vasopressin analogues is the potential for ischemia, which has been shown to be clinically significant with only ornipressin. Terlipressin is not currently available in the United States, however (29).
The combination of octreotide and midodrine has been shown to have some beneficial effects on renal function and mortality in HRS; however, patients treated with vasopressin had improved survival rates and were more likely to receive a liver transplant (31). There is no literature that has investigated the combined effects of all three agents. In a very small study, norepinephrine had comparable efficacy to vasopressin without any adverse side effects (32). In patients with liver failure who develop hypotension, norepinephrine and vasopressin are agents that should be considered first line with less concern regarding renal side effects. Patients who do not respond to the above therapies will likely require some form of renal replacement therapy. Continuous venovenous hemodialysis (CVVHD) is the treatment of choice since it causes less hypotension, with a decreased potential to create ongoing injury compared to hemodialysis performed 3 times a week. However, once a patient has received any type of dialysis for HRS lasting longer than 12 weeks, there is a risk that renal dysfunction will either continue after transplantation or will recur within a few years. For patients who develop renal failure within 13 years of their liver transplant, survival is only 28% compared to 55% for those who do not; yet, it is not clear which patients will definitely develop ongoing renal compromise. Therefore, the selection of which patients will receive a combined liver/kidney transplant remains in evolution (33).
Fulminant Hepatic Failure
The abrupt onset of liver failure within 8 weeks in a previously healthy patient has been the traditional definition of fulminant failure, but modern discussion centers on potentially decreasing the time period to 2 weeks to correlate with the prognosis. There are several potential causes, but acetaminophen is by far the most common. The mortality rate is 80% without liver transplantation (34).
Table 93.2 summarizes the King's College criteria for liver transplantation (35). The MELD score has a higher sensitivity and negative predictive value, but a very high false-positive rate so it may be better to use it in conjunction with King's College criteria to avoid transplantation in patients who may recover spontaneously (36). One of the main components of both scores is the prothrombin time and/or INR. Therefore, it is imperative to give blood products only if bleeding occurs or a procedure is planned. Infection occurs in 80% of patients with fulminant hepatic failure (FHF), and thus a high index of suspicion and regular surveillance are important. Some centers use prophylactic antibiotics, but this increases the risk of fungal infections, which occur in 30% of patients with FHF. Hemodynamically, FHF is associated with a high cardiac output and vasodilation similar to sepsis, making infection difficult to discern. Optimizing intravascular volume is the main goal in management, but vasopressors may be necessary. Fluid management may be complicated by renal failure since this occurs in 40% to 50% of patients (34).
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Table 93.2 King's College Criteria for Liver Transplantation In Fulminant Hepatic Failure |
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Table 93.3 Hepatic Encephalopathy in Fulminant Hepatic Failure |
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Encephalopathy inversely correlates with prognosis. Table 93.3 summarizes the four stages of encephalopathy that are seen in FHF (34). Cerebral edema occurs in most cases that progress to stage 4. Typical symptoms of cerebral edema are the Cushing reflex, decerebrate rigidity, dysconjugate eye movements, and a loss of pupillary reflexes. Intracranial pressure (ICP) monitoring should be considered if the patient develops stage 3 or 4 encephalopathy due to the development of increased ICP in the setting of systemic hypotension (34). Cerebral perfusion pressure (CPP) of >60 mm Hg is necessary to maintain intact neurologic function. Liver transplantation in the setting of CPP <40 mm Hg for 2 hours or more is contraindicated (37). Concern for intracranial bleeding associated with the placement of an ICP monitor has precluded use in most liver transplant centers. Recently, factor VIIa has been shown to be effective in transiently correcting coagulopathy to allow for safer placement of this monitor (38). Patients with elevated ICP are candidates for mannitol, mild hyperventilation, and barbiturate or propofol infusions while maintaining systemic blood pressure in an attempt to optimize CPP.
Anesthetic and Surgical Issues
Anesthetic Drugs
Increasingly, numerous transplant centers demonstrate successful extubation at the end of surgery in over 50% of patients (39). Therefore, careful dosing of anesthetic drugs is warranted to ensure the possibility that patients are awake enough to extubate. Low doses of midazolam based on previous history of exposure to benzodiazepines and alcohol and less than 20 µg/kg of fentanyl will facilitate avoidance of postoperative mechanical ventilation in suitable patients who are able to maintain oxygenation and normocarbia. Maximizing the use of inhaled agents will decrease the need for other sedative agents. Isoflurane is probably the volatile anesthetic of choice to preserve splanchnic flow, as it produces vasodilator effects on the hepatic circulation (1). Cisatracurium is the muscle relaxant of choice since it is degraded by serum esterases. Some reports suggest that a recovery time of more than 150 minutes from rocuronium is predictive of primary graft dysfunction (40).
Blood Product Use
Patients with liver failure have a decrease in all factors except von Willebrand. Platelets are also reduced secondary to hypersplenism, bone marrow suppression, and decreased thrombopoietin production in ESLD (41). Attempts to correct coagulation defects in patients undergoing liver transplantation result in a hypervolemic state, which can lead to an increase in blood transfusion. Restricting the transfusion of products to situations in which clinical bleeding requires control or to treat severe anemia can lead to fewer or no red blood cell transfusions during liver transplantation. This has been shown to improve 1-year survival after transplantation (42). Table 93.4 is a transfusion algorithm based on the thromboelastogram and has been applied successfully in cardiac surgical patients to decrease transfusion (43). Some minor changes make it amenable to liver transplantation patients. Thromboelastography is used because most serum component markers of coagulation do not reflect the intricate dynamics of whole blood clotting to guide transfusion.
Aprotinin use in liver transplantation has been shown to decrease red blood cell transfusion in several randomized trials (44,45). During the anhepatic phase of surgery, the suprahepatic and infrahepatic vena cava may be cross-clamped. This is a stage during which there is rapid increase in tissue-type plasminogen activator in the absence of α-2-antiplasmin and plasminogen activator inhibitor. Therefore, plasmin activity increases, and fibrinolysis can ensue (46). Aprotinin acts to inhibit plasmin. The concern regarding the use of aprotinin on a prophylactic basis is due to scattered case reports of thrombotic episodes such as clots on pulmonary artery catheters and an increased rate of vein graft occlusions in cardiac surgery (47).
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Table 93.4 A Thromboelastogram-based Algorithm in Liver Transplantation |
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Stagnation of blood flow can lead to clot formation in the vena cava. On reperfusion of the transplanted liver, echocardiographic evidence of embolization has been documented, even in the absence of aprotinin (48). Nonetheless, it is concerning that there are several case reports of massive pulmonary embolism and death during liver transplantation when aprotinin was used (49,50). Given the crude understanding of coagulation in the presence of liver disease, potential aprotinin administration should be reserved for documented fibrinolysis during the reperfusion stage. The lowest effective dose documented in the literature is 500,000 kallikrein inactivation units (KIU) as a bolus, with 150,000 KIU/hour, with equal efficacy to higher doses in limiting the number of blood products transfused (51). If pulmonary embolism occurs, supportive care and thrombolysis may lead to better outcomes compared to embolectomy (50).
The benefit of aprotinin outside of blood conservation includes potential anti-inflammatory activity. Aprotinin has been shown to decrease some of the cytokines that inappropriately vasodilate patients with ESLD such as TNF and nitric oxide (52). This can produce less cardiovascular instability and vasopressor use, and result in improved graft function (46). However, there are several adverse effects with increasing documentation in the cardiac surgery literature. Recent evidence suggests a dose-dependent increase in death, renal failure, and cardiovascular events when aprotinin was used. This information makes routine or even occasional use of aprotinin questionable for reasons other than thromboembolic complications (53).
Aminocaproic acid and tranexamic acid have both been used in liver transplantation but are less studied than aprotinin. There are fewer randomized controlled trials to confirm efficacy. Furthermore, neither agent has the benefit of the anti-inflammatory activity, which is seen with aprotinin. These agents exert their effect by inhibiting the conversion of plasminogen into plasmin (46). In studies with aminocaproic acid, fatal thromboembolism has occurred if the standard dose in cardiac surgery is given with a 5-g bolus and then 1 g per hour. However, it has been safely used without reports of many thromboembolic complications if administered in lower doses, ranging from 0.25 to 1 g as a bolus only. Success was variable in controlling significant bleeding (46). Studies with tranexamic acid have shown a dose-related effect. Low dose (2mg/kg/hour) has minimal effect on transfusion requirements, but high dose (10–40 mg/kg/hour) has been shown to significantly reduce intraoperative bleeding. An optimal dose has not been established (46). Tranexamic acid has not been associated with thromboembolic phenomena, but it is much less frequently used than either aprotinin or Amicar to treat fibrinolysis during liver transplantation.
Factor VIIa is a novel way to increase the thrombin burst and acutely improve coagulation on a short-term basis secondary to rapid factor consumption. Theoretically, it requires an activated platelet so coagulation occurs at the site of bleeding and not systemically (54). It has been studied in cirrhotic patients in trials for gastrointestinal bleeding and liver transplantation (55,56,57). Neither showed any difference in the degree of bleeding or required transfusions. However, cirrhotic patients are likely to be factor VII deficient. There has been no dose-ranging study to look at efficacy related to the degree of serum levels achieved.
Fluids and Electrolytes
Along the lines of avoiding hypervolemia, minimizing fluid use is the goal during liver transplantation. There is no particular type of fluid that conclusively shows benefit. ESLD patients have a decreased ability to metabolize lactate and are prone to lactic acidosis, especially during the required interruption of blood flow for performing the vascular anastomosis of the liver transplant (58). The exclusive use of lactate-containing solution is likely unwise. In addition, patients may require a small amount of bicarbonate administration to offset ongoing acid production, with attention to the fact that large amounts will result in metabolic alkalosis after surgery (58). Placing 150 mEq of sodium bicarbonate in 1 L of D5W achieves an isotonic fluid with a modest degree of bicarbonate. Using this fluid during the anhepatic phase of surgery may have the added benefit of aiding renal preservation. ESLD patients experience renal vasoconstriction that may be similar pathophysiologically to what occurs with intravenous dye administration (59).
Hyponatremia at ≤127 mEq/L occurs in 3.5% of liver transplant candidates. A change in serum sodium approaching 20 mEq/L is much more likely to produce central pontine myelinolysis (CPM) than a change closer to 7 mEq/L (60). CPM is a source of mortality after liver transplantation (61). Normal saline solutions are actually somewhat hypernatremic and hyperchloremic to serum, and excessive use will lead to hyperchloremic acidosis. Albumin administration has shown benefit during paracentesis and in the long-term management of patients with ESLD. However, there is no conclusive evidence for risks or benefits during liver transplantation, and it is a source of sodium as well. Although a transfusion algorithm will minimize administration, fresh frozen plasma may be required in some amount and also presents a salt load. Potentially, a mixture of crystalloid and colloid provides the best approach.
Attempting to maintain euvolemia in patients who are total body-volume overloaded leads into a discussion of diuretic administration. Intravascular volume depletion chronically present in ESLD complicates the use of furosemide unless there has been significant volume overload requiring removal such as a stable patient who required several different blood products to control bleeding. However, mannitol has many characteristics that make it advantageous to use during liver transplantation. Patients with ESLD may have edema of the abdominal organs due to congestion of blood flow through the fibrosed liver and the hypoalbuminemic state. The osmotic activity of mannitol can aid in removing free water within these organs, particularly in the setting of hepatorenal syndrome, and thus prevent hepatic distention once the transplanted liver is reperfused. It may also provide some renal protection during hypoperfusion of the anhepatic stage while simultaneously increasing portal blood flow. Finally, the patient benefits from the potential of mannitol to provide free radical scavenging (62). Optimal dosing of mannitol is 0.5 to 1 g/kg just prior to cross-clamping or while anhepatic.
In addition to acid-base homeostasis, there are a number of other electrolyte issues of concern during liver transplantation. Due to the presence of cirrhosis-induced insulin resistance, the increase in stress hormones during surgery, and the use of steroid and glucose-containing solutions, patients may become quite hyperglycemic even if there are no glucose control issues prior to surgery (58). Since these patients are going to the intensive care unit, they may benefit from some degree of control with an insulin infusion, with the goal of maintaining the blood sugar >80 mg/dL and <150 mg/dL. With the use of diuretics and the presence of malnutrition, magnesium deficiency is also common in liver failure (58). This places the patient at risk for arrhythmias, which can be resistant to treatment without magnesium replacement (63). In addition, in some patients a hypocoagulable tracing on a thromboelastogram (TEG) has been shown to normalize solely from magnesium supplementation (64). Patients can be hyperkalemic or hypokalemic prior to liver transplantation also based on the degree of diuretic use; hyperkalemia can be exacerbated during surgery, especially since spironolactone has such a long half-life. Transfused blood products are a source of additional potassium during surgery. Depending on the type of preservation solution, revascularization can be a time of excessive hyperkalemia, which can result in cardiac arrest (65). This concern is increased with livers obtained through donation after cardiac death, with resultant warm ischemia and increased cell death.
Patients with significant renal dysfunction and/or those undergoing dialysis at the time of transplantation will most likely require CVVHD during liver transplantation. Although this is helpful to manage electrolyte abnormalities, it is not quick. This is particularly the case with metabolic acidosis in which patients often require the addition of a dilute bicarbonate infusion, which may be faster and safer (66). However, CVVHD can be used to both remove and administer fluid expeditiously. A heating system should be used during CVVHD since serum is exchanged at about the rate of 22 to 30 L in 24 hours, and patients can become hypothermic, which can exacerbate baseline coagulopathy. To prevent the system from developing clots, citrate is often used, as opposed to heparin, in patients with significant coagulopathy. Between this condition and the amount of citrate that may be administered from blood products, calcium supplementation is often required (58).
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Figure 93.1. Piggyback technique. (From Eghtesad B, Kadry Z, Fung J. Technical considerations in liver transplantation: what a hepatologist needs to know (and every surgeon should practice). Liver Transpl. 2005;11[8]:861–871, with permission.) |
Surgical Considerations
In the past, venovenous bypass was required for the anhepatic phase of liver transplantation due to the patient's inability to tolerate complete occlusion of the portal vein and inferior vena cava. However, this intervention is not without the potential for complications such as nerve damage and lymphatic disruption, as well as fatal pulmonary embolus (2). The piggyback technique (Fig. 93.1), in which outflow of the donor liver is anastomosed to a vessel formed from combined hepatic veins, results in a shorter anhepatic phase and avoidance of completely cross-clamping the inferior vena cava. The advantages in addition to avoiding venovenous bypass include less bleeding, protection of renal venous outflow, less adrenal injury, and potentially more hemodynamic stability (2).
Cardiopulmonary Management
Intraoperative transesophageal echocardiography (TEE) has increasingly been used as part of an anesthetic in situations that traditionally have been managed with a pulmonary artery catheter. There are no randomized controlled trials demonstrating the efficacy of this technology in liver transplantation. However, it would seem helpful at the time of reperfusion given that cardiac output alone is not as reliable in patients with liver failure and the potential presence of cirrhotic cardiomyopathy. It would also document evidence of thromboembolism during that stage of the surgery. The obvious concern about the use of TEE is the risk of bleeding from varices. No case reports have documented this as an actual risk, and there are some centers that use TEE on a regular basis. Theoretically, varices may deflate after celiotomy, with resultant decrease in abdominal pressure. It would seem prudent to evaluate the use of the technology on a case-by-case basis and maybe restrict its use to an unstable patient (67).
Minimizing intrathoracic pressure will be helpful to improve hepatic outflow. Setting lower tidal volumes (6–8 mL/kg) and avoidance of positive end-expiratory pressure may contribute to maintaining euvolemia in minimizing preload, and therefore decrease the risk for bleeding. Nitric oxide has been shown to improve oxygenation and decrease severe intraoperative pulmonary hypertension (68) as a bridge to more definitive treatment. However, the most commonly used medication for intraoperative therapy of pulmonary hypertension is epoprostenol.
Patients frequently require the use of vasopressor agents. As already discussed above, vasopressin and norepinephrine are considered the best choices due to their potential to improve intra-abdominal vascular stability and enhance renal perfusion without inducing mesenteric ischemia. Since the phenomenon of cirrhotic cardiomyopathy is difficult to demonstrate, there are no studies on the beneficial effects of dobutamine or milrinone.
Posttransplant Complications
The postoperative goals in a liver transplant recipient are similar to intraoperative priorities. Therefore, this section will discuss unique and specific postoperative entities. Infections in the immunodepressed posttransplant period are thoroughly discussed in other sections of the textbook.
Primary Nonfunction
Ischemia reperfusion injury of the transplanted organ can result in some degree of graft dysfunction, which can be compensated by the significant regenerative capacity of the liver. However, some patients may develop primary graft nonfunction, with a reported incidence of 7% (69). There is no clear definition or uniform diagnostic criteria for this diagnosis, but generally it includes patients who die or require retransplantation within 1 week without a definite technical or immunologic cause. Patients appear to rapidly go back into hepatic failure with high levels of aminotransferases, prolonged prothrombin time, hepatic encephalopathy, hypoglycemia, and lactic acidosis (70).
Reactive oxygen intermediates and issues in organ preservation represent targets to potentially modulate primary nonfunction, but there are currently no definitive preventative strategies or treatments. Donor age older than 50 years and macrovesicular steatosis of >60% are possible risk factors, but these have not been shown to be consistently so (70).
Vascular Occlusion
Studies concerning the incidence of portal vein thrombosis (PVT) at the time of liver transplant show that it occurs in about 12% of patients. The presence of a pre-existing thrombosis makes surgery more challenging and increases the risk of rethrombosis after transplantation, but it has not been shown to alter mortality (71). The incidence of PVT presenting after transplantation is less than 1%. In addition to a prior history of PVT, the risk factors include a hypercoagulable state, perioperative hypotension, and allograft cirrhosis. Acutely, it can lead to hepatic failure, but chronically there is a more insidious presentation involving portal hypertension with ascites and varices (70). Hepatic vein thrombosis is very unusual except in patients who have undergone transplantation for Budd-Chiari syndrome with subtherapeutic anticoagulation, and it typically takes months to years to develop (70).
The most common vascular complication is hepatic artery thrombosis (HAT), which occurs somewhere between 3% and 9% (72). In addition, mortality is common without retransplantation, with an incidence of about 30% (70). If HAT is tolerated by the liver surviving solely on portal flow, then complications occur usually after 1 month with the development of bile duct strictures since virtually all biliary perfusion comes from the hepatic artery. For patients who cannot be supported solely on portal flow, their presentation is much more acute with severe graft dysfunction or primary nonfunction (70).
Risk factors for HAT include small caliber or complex arterial structure of both the donor and recipient. Increased donor age and a recipient/donor ratio greater than 1.25 can put the recipient at risk for HAT. Medical issues that may predispose to HAT include cytomegalovirus infection, rejection, tobacco use, and hypercoagulable states. Urgent revascularization can be attempted for early presentation of HAT-associated graft dysfunction (70). This can be accomplished angiographically or surgically. However, about 50% of patients in this scenario will require retransplantation. Patients who do receive some type of intravascular therapy have difficulty maintaining long-term hepatic artery patency (72).
Rejection
Not only is rejection less common in liver transplantation than in other solid organ transplants, but less rejection occurs in the latter group when performed in the setting of a concurrent or previous liver transplant (73). In addition, rejection that occurs early after the liver is transplanted does not necessarily affect overall graft survival (74). This effect is not due to antigenic indifference, but instead to an active immune system process in which there are several theoretical causes. Microchimerism is one such hypothesis where donor hematopoietic cells persist in the recipient, producing tolerance through a balance of graft versus host and host versus graft reactions (73).
Nonetheless, transplantation tolerance is not attainable consistently. It has been shown that patients can be weaned off corticosteroid immune suppression 3 to 4 months after transplantation, but complete cessation of immune suppression is associated with about a 30% incidence of rejection (74). The commonly used immune suppressives in liver transplantation with their side effects are listed in Table 93.5 (75). Side effects can result in the alteration of which medications are used, and the development of a lymphoproliferative disorder can be grounds for complete cessation of therapy (73).
Acute rejection occurs within the first 5 to 15 days after transplantation. It is manifested by fever, graft enlargement, tenderness, leukocytosis with increased eosinophils, and reduced bile production. Biopsies are done only when symptoms are present because the morphologic features consistent with acute rejection can be present in a significant percentage of patients in the early posttransplant period (76). Treatment for acute rejection is 3 to 5 days of 500 to 1,000 mg of methylprednisolone daily, with about 75% resolution. A second course is sufficient for treatment in an additional 10%. The rest require some type of antilymphocyte therapy, with a rare case requiring retransplantation (77). Patients who develop rejection in the setting of complete immune suppressive cessation have been shown to have an increased risk of steroid-resistant rejection (74).
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Table 93.5 Immune Suppressive Medication in Liver Transplant |
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Biliary Dysfunction
Posttransplant complications in the biliary tract are relatively common. The reported incidence is somewhere between 9% and 15% (78). A very rare syndrome of diffuse biliary necrosis may require retransplantation. In this scenario, patients present with a combination of sepsis, cholestasis, and bile leakage in which temporizing measures are useless. However, most cases of biliary dysfunction are not a cause for retransplantation or mortality (78).
Early complications of the biliary tract are leaks and strictures. Anastomotic leaks and strictures are the most serious and are usually related to ischemic necrosis of the donor distal bile duct. These can be managed with endoscopic or percutaneous stenting and require surgery only if a major leak is present. The vast majority of these problems present within the first 2 months after transplantation (78).
Live Donor or Living Related Liver Transplantation
For the most part, the recipient receives essentially the same measures. However, there is an increased risk of vascular and biliary problems postoperatively. Unique to this type of transplantation is small-for-size syndrome. Essentially, the patient has poor bile production, delayed synthetic function, prolonged cholestasis, and intractable ascites. These patients are at risk for sepsis and have an increased mortality (79). A similar situation may affect patients who receive a split liver as well.
Summary
The patient undergoing liver transplantation has a significantly altered physiology and undergoes specific management to ensure optimal outcome. Coordinated care from the perioperative physician, surgeon, and anesthesiologist can minimize the risks from this procedure so the intensivist is in the position to effect a prognosis.
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