Abstract
Orthotopic liver transplantation is the only definitive treatment for end-stage liver disease. More than 6000 procedures are performed in the United States annually with excellent survival rates. The shortage of donor organs leads to continued interest in techniques to enlarge the potential donor pool. Patients presenting for liver transplant suffer from important cardiovascular, respiratory, renal, neurological, and gastroenterological comorbidity. In the Western world, liver failure is increasingly caused by steatohepatitis, and transplant candidates are thus becoming older and more comorbid. The role of the transplant anesthesiologist is highly important in the preoperative assessment, intraoperative management, and postoperative care of these complex and sick patients. Appropriate investigation and management of comorbidities such as coronary artery disease and portopulmonary hypertension is controversial and differs between programs. The transplant procedure is a major surgery, and although massive transfusion is no longer commonplace, there is potential for significant hemodynamic instability, coagulopathy, and metabolic disturbance. Liver transplant surgery can be divided into the preanhepatic phase, the anhepatic phase, and the reperfusion phase, with important anesthetic considerations at each point. An understanding of the surgical techniques used for vascular exclusion of the liver and the role of venovenous bypass is crucial for the anesthesiologist. Recent trends in perioperative care include the use of antifibrinolytic drugs and point-of-care coagulation tests, intraoperative renal replacement therapy, and “fast-track” extubation and postoperative care. Care of patients with fulminant hepatic failure or those receiving split-liver grafts requires special consideration.
Introduction
Since it was first successfully performed by Starzl in 1967, orthotopic liver transplantation has become established as the only definitive treatment for end-stage acute and chronic hepatic failure. 1 This article will review the fundamental principles underpinning the practice of anesthesia for liver transplantation and touch on recent developments within this challenging subspecialty.
Indications for Liver Transplantation
The indications for liver transplantation in the modern era are broad but can be organized into 7 major categories 2 :
noncholestatic cirrhosis, usually from alcoholism, chronic viral hepatitis, or nonalcoholic steatohepatitis;
cholestatic liver disease, such as primary biliary cirrhosis and primary sclerosing cholangitis;
biliary atresia;
acute hepatic necrosis caused by drugs such as acetaminophen, acute infective causes such as hepatitis B, and liver transplant graft dysfunction/nonfunction;
metabolic disease, such as hemochromatosis;
malignant neoplasm, primarily hepatocellular carcinoma and cholangiocarcinoma; and
other causes such as Budd-Chiari syndrome.
Typically patients with chronic liver disease are referred for consideration for liver transplantation once they experience decompensation, such as ascites, hepatic encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, and hepatorenal syndrome, or when they develop concurrent hepatocellular carcinoma. 3 Referral may be expedited in the setting of concurrent carcinoma or other superimposed or associated disease, which is likely to adversely affect survival.
Liver Transplantation in North America
Chronic liver disease accounts for more than 750,000 hospitalizations per year in the United States. 3 Each year, more than 40,000 patients progress to end-stage liver disease, liver failure, and death. 3 Acute (fulminant) hepatic failure affects approximately 2000 people in the United States annually and accounts for 5% to 6% of all liver transplants. 3
Liver transplantation in the United States is coordinated by a not-for-profit organization called the United Network for Organ Sharing (UNOS). UNOS maintains the waiting list for patients awaiting liver transplant, ranks patients according to priority, and allocates donor organs. 2 As of January 3, 2013, there were 15,934 candidates on the UNOS waiting list requiring liver transplantation. In 2011, 6342 liver transplants were performed in the United States. Of these, 6095 were from cadaveric donors and 247 from living donors. 2
Currently, liver transplantation recipients in the United States achieve 1-, 3-, and 5-year patient survival rates of 87%, 78%, and 73%, respectively, with remarkable consistency across the various programs. 3 Unfortunately, because of organ shortages, about 5% to 10% of patients listed for a liver transplant will die without receiving an organ. 3
UNOS uses a scoring system to prioritize patients to receive liver transplants, called the Model for End Stage Liver Disease (MELD) score. This is a validated system that uses serum total bilirubin, serum creatinine, and international normalized ratio (INR) values to mathematically rank adult patients awaiting liver transplant according to their expected survival rates without transplant. 3 The Child-Turcotte-Pugh score is a historical method of grading the severity of chronic liver disease based on the allocation of points for grade of encephalopathy, severity of ascites, serum bilirubin, prothrombin time (PT), and serum albumin. 4 The Child-Pugh-Turcotte score has largely been superseded by the MELD. An Internet calculator for MELD score provided by UNOS can be found at http://optn.transplant.hrsa.gov/resources/MeldPeldCalculator.asp.
The Physiological Effects of Liver Disease
The Cardiovascular System
There is an interdependent relationship between the function of the heart and the liver. 5 Cardiac failure can provoke hepatic congestion and damage. 6 In patients with cirrhotic liver disease, there are unique cardiac problems that can arise. Additionally, systemic illnesses can simultaneously cause both liver and heart problems, such as alcoholism (causing both cirrhosis and cardiomyopathy). Finally, there are “baseline” cardiac diseases found incidentally in the liver transplant candidate, which also commonly occur in the normal population. 5
Cardiac dysfunction
The patient with end-stage liver disease displays characteristic hemodynamic changes. 6 Typically, the patient has a high cardiac output, with high resting heart rate and relatively low blood pressure. In patients with cirrhosis, because of reduced hepatic metabolism, there are thought to be endogenous mediators in hepatic portal blood that “spill over” into the systemic circulation and cause profound splanchnic vasodilation and thus reduced systemic vascular resistance. 7 There is compensation by the cardiovascular system, with activation of the renin-angiotensin system to preserve mean arterial pressure and renal perfusion, at the cost of increased intravascular volume.
There is also increased sympathetic activation and high circulating levels of catecholamines. 7 In these patients with “hyperdynamic circulation,” there is a temptation to assess cardiac ventricular function as adequate: however, the reduced cardiac afterload in this setting may mask what is in fact, reduced underlying cardiac function. 8 There is a subset of patients with liver failure who, despite having no overt evidence of cardiac failure and a relatively high resting cardiac output, have a blunted ventricular systolic response to stress. Known as cirrhotic cardiomyopathy, there is also ventricular diastolic dysfunction and electrophysiological abnormalities such as chronotropic incompetence and a prolonged QT interval. 8 Abnormal electromechanical coupling of the cardiac myocyte may be the cause of these patients’ stiff, noncompliant, and less-efficient ventricles, which perform poorly with increased work. 8 The implications of this form of cardiac dysfunction in terms of perioperative and long-term recovery following liver transplantation is unclear. 8
Coronary artery disease (CAD)
Historically, it was believed that patients with cirrhosis, with their observed tendencies to have low blood pressure, low cholesterol levels, and increased estrogen levels, were physiologically protected against CAD. More recent evidence has refuted this assertion. 9 The assessment and management of liver failure patients with CAD is currently one of the most controversial areas in the field.
Since the publication of Plotkin’s work 10 in 1996, it has been clear that patients with preexisting CAD suffer increased rates of perioperative and postoperative morbidity and mortality with liver transplantation. However, the past 2 decades have seen dramatic progress in the way anesthesiologists identify, investigate, and risk stratify patients with CAD presenting for noncardiac surgery. Plotkin’s publication suggested that in the setting of significant CAD, 3-year survival following liver transplant was as low as 50%, with a 12.5% rate of intraoperative death. 10 Subsequent work in the area has revealed that CAD, both overt and occult, occurs at least as commonly in the pre–liver transplant population as it does in matched controls and that, when present, CAD predicts poor outcome.11,12 However, since the 1990s, there have also been major advances in the way patients with CAD are treated, including more aggressive medical therapy, and evolution in both open and percutaneous revascularization. 13 It is interesting to note that patients in whom end-stage liver failure is caused by ethanol may be relatively protected against the development of CAD, whereas patients with nonalcoholic fatty liver disease/steatohepatitis likely are at increased risk of coronary atheroma compared with other end-stage liver disease patients.14,15 With North America currently facing an aging population and an “obesity epidemic,” the number of patients with nonalcoholic steatohepatitis presenting for liver transplant assessment is likely to increase. We can thus expect to see an increasing prevalence of CAD in liver transplant candidates. 16
The right-heart and portopulmonary hypertension
Patients with severe liver disease are at risk of developing raised pressures in their pulmonary vasculature. The pulmonary vasculature is a capacitance system, with high blood flows, low pressure, and low vascular resistance. 17 Resting mean pulmonary artery pressure greater than 25 mm Hg is classified as pulmonary hypertension. 17 Liver patients with raised pulmonary artery pressures can have either normal or abnormally raised pulmonary vascular resistance. Pulmonary hypertension with raised pulmonary vascular pressures (>240 dyne s cm−5) in the setting of portal hypertension is classified as portopulmonary hypertension and is a marker of poor outcome for liver transplant. 18
This, however, must be distinguished from the 30% to 50% of patients with end-stage liver disease who have elevated pulmonary artery and venous pressures with normal pulmonary vascular resistance. This is a normal finding in the hyperdynamic liver transplant candidate and no contraindication to transplantation. 19 Conversely, the pathological finding of portopulmonary hypertension occurs in 6% to 8% of patients with cirrhosis. 18 The pathophysiology of the condition is unclear, but it may have a genetic basis. 18 The vascular changes that occur include the development of intimal proliferation and medial hypertrophy in pulmonary arteries, which, when combined with thrombosis, may cause narrowing of the lumen. 18 Initially, these changes may be overcome with vasodilator therapy but with time become fixed with fibrosis. 17
The right ventricle is a thin-walled chamber that is designed for volume rather than pressure work. 17 If increases in pulmonary artery pressures develop slowly over time, there is potential for the right ventricle to hypertrophy and cope with the added work, whereas if the changes are more rapid, or in the setting of decreased right-ventricular contractility, right-ventricle failure will occur. 17
Portopulmonary hypertension has been classified into mild (mean pulmonary artery pressure 25-35 mm Hg), moderate (35-45 mm Hg), or severe (>45 mm Hg). There seems to be no increased perioperative risk for liver transplant candidates with mild portopulmonary hypertension, whereas moderate and severe disease is associated with increased perioperative mortality. Patients with severe portopulmonary hypertension have been reported to have mortality rates as high as 42% at 9 months. 20
It is generally accepted that severe, untreated portopulmonary hypertension is a contraindication to liver transplantation. 18 What is less clear is the role of pulmonary vasodilators, including calcium channel blockers, prostanoids such as prostacyclin, phosphodiesterase inhibitors such as sildenafil, and endothelin receptor antagonists, as a preparation for surgery. 18 Many centers will accept patients for liver transplant who respond to a therapeutic trial of pulmonary vasodilators. Also important in the assessment of perioperative risk for patients with raised pulmonary artery pressures is consideration of the underlying right-ventricular function.
The Respiratory System
The majority of patients with end-stage liver disease complain of dyspnea. 19 There are multiple mechanisms whereby advanced liver disease can adversely affect respiratory function. Additionally, many liver transplant candidates are smokers or are prone to lung pathology unrelated to their liver disease.
Hepatopulmonary syndrome
This is a syndrome characterized by onset of dyspnea and platypnea-orthodeoxia in patients with significant liver disease. 19 Platypnea-orthodeoxia is a paradoxical increase in breathlessness and decrease in arterial partial pressure of oxygen, when a patient moves from the supine to the upright position because of abnormal pulmonary vessel size. 19 The characteristic anatomical lesion is an increase in precapillary and capillary pulmonary vessel caliber from a normal diameter of less than 15 µm to up to 100 µm. 19 This intrapulmonary vascular dilation leads to increased pulmonary vascular blood flow without increased alveolar ventilation, causing V/Q mismatching, plus a degree of intrapulmonary shunting of deoxygenated, mixed venous blood through the lungs. 19 Both these mechanisms cause systemic arterial hypoxemia. In severe cases the pulmonary vasodilation is significant enough itself to cause alveolar capillary oxygen diffusion limitation. 19 There is impairment of pulmonary vascular tone in response to hypoxemia (hypoxic pulmonary vasoconstriction), meaning that gravitational effects on pulmonary blood flow are poorly tolerated, leading to the classical presentation of platypnea-orthodeoxia. 19 Hepatopulmonary syndrome can be classified according to the severity of arterial hypoxemia, with arterial partial pressure of oxygen (on room air) of 60 to 80 mm Hg, representing mild, 50 to 60 mm Hg moderate, and <50 mm Hg defining severe hepatopulmonary syndrome. 19
There is no known pharmacological therapy to treat hepatopulmonary syndrome. The outcome of patients with hepatopulmonary syndrome complicating their end-stage liver disease who do not receive liver transplants is poor. 19 This fact is recognized by UNOS exception status with increased points being applied in the MELD system to patients with hepatopulmonary syndrome awaiting transplant. 21 Patients with hepatopulmonary syndrome fare less well following liver transplant; however, the results are acceptable. 19 There is usually resolution of the symptoms and signs of hepatopulmonary syndrome following liver transplant, though this can be variable and take some months to occur. 19
Hydrothorax and ascites
A common complication of liver disease and portal hypertension is the accumulation of ascites in the abdomen. Whereas the presence of abdominal ascites itself sometimes compromises respiratory function, a more significant complication is the presence of ascitic fluid in the thorax, termed hepatic hydrothorax. This complication is seen in up to 10% of patients with ascites, is usually right sided, and is thought to be caused by migration of fluid through small diaphragmatic defects. 19 Patients may complain of shortness of breath or cough and exhibit tachypnea and hypoxemia. 19 Ultrasound examination may aid diagnosis and therapeutic thoracocentesis. 19 It is a reasonable practice to arrange preoperative drainage of large hydrothoraces with obvious respiratory compromise, whereas smaller fluid collections often resolve at surgery with the drainage of ascites.
The Renal System
Acute kidney injury is a common complication of advanced cirrhosis because there is a powerful relationship between hepatic and renal dysfunction. 22 The most severe form is seen in the hepatorenal syndrome. This syndrome is a form of prerenal failure that occurs in patients with severe chronic liver disease. Blood accumulates in the grossly dilated splanchnic vasculature, effectively causing arterial intravascular volume depletion. 22 This leads to reduced arterial blood volume, low systemic arterial pressure, renin-angiotensin release, sympathetic system activation, renal vasoconstriction, low renal perfusion, and low glomerular filtration rate (GRF). 22 Serum creatinine is raised, and this correlates strongly with pretransplant death, hence the role of creatinine in the MELD criteria used for prioritization of liver recipients. Hepatorenal syndrome is divided into 2 subtypes. 23 Type I hepatorenal syndrome is the more severe manifestation, with a rapid decline in glomerular filtration rate and a median survival of only 2 weeks. Type II is associated with a more moderate and progressive reduction in renal function, and patients have survival measured in months. 23 Hepatorenal syndrome needs to be differentiated from other forms of acute renal dysfunction in liver disease, most often acute tubular dysfunction from hypovolemia, for example, in the setting of gastrointestinal bleeding, or from drug toxicity or infection such as spontaneous bacterial peritonitis.
If renal dysfunction causes uremic symptoms or hyperkalemia, various forms of renal replacement therapy are typically instituted. 22 The presence of ascites usually renders peritoneal dialysis unfeasible. Furthermore, patients with hepatorenal syndrome are already prone to hypotension and poorly tolerate the fluid shifts and blood pressure changes associated with hemodialysis. In this setting, continuous renal replacement therapy is the best option and allows more stable hemodynamics. 24 If renal function is particularly poor or the patient unstable, it may be prudent to continue renal replacement therapy in the operating room.
The Neurological System
Patients with chronic liver disease commonly suffer from symptoms of hepatic encephalopathy. This may be manifest by symptoms that range from mild apraxia and behavioral changes, to decerebrate posturing and coma. 25 A distinction is often made between the acute, rapidly progressive syndrome associated with acute liver failure and the chronic or episodic symptoms seen in patients with cirrhosis. 25 The pathophysiology of hepatic encephalopathy is very complex and poorly understood. Bacterial breakdown of nitrogen metabolism in the gut produces ammonia, and the impaired metabolism of ammonia in liver disease is thought to cause ammonia levels to be elevated in the brain, with serum ammonia being some guide to the level of encephalopathy. 25 However, there is only a rough correlation between ammonia levels and brain function, and the metabolism and function of neurotransmitters such as glutamate, glutamine, serotonin, lactate, and pyruvate are also implicated in brain dysfunction. 25 Therapies for treatment include the use of nonabsorbable disaccharides such as lactulose, which, it is thought, reduce encephalopathy by affecting bacterial function in the colon and thereby reducing the enteric production of ammonia. 25 Other management involves reducing the nitrogen load in the gut by minimization of gastrointestinal bleeding, reducing dietary protein, correcting or minimizing electrolyte and metabolic abnormalities, and judicious use/avoidance of sedative drugs, especially benzodiazepines. 25 Antibiotics such as metronidazole and rifaximin are also used to decrease bacterial activity in the gut. 25
In acute liver failure, hepatic encephalopathy is often accompanied by cerebral edema, which is rare in the encephalopathy of chronic liver failure. In severe encephalopathy of acute liver failure, more than 65% of patients will have brain edema and variable degrees of intracranial hypertension. 25 The reason for the formation of cerebral edema is poorly understood, although serum ammonia and formation of cerebral free radicals at a cellular level are implicated. 26 These patients need invasive ventilation and neuro-oriented intensive care.
The Hematological System
Patients with severe liver disease often exhibit abnormal tests of hemostasis. The PT or INR, and the activated thromboplastin time (APTT) are often significantly prolonged. 27 Additionally, there is often thrombocytopenia as a result of splenomegaly and sequestration of platelets despite normal or even increased production. 28 A traditional view is that the failing liver cannot produce sufficient levels of coagulation factors and that the abnormal coagulation tests reflect a baseline hypocoagulable state. 28 However, this is probably an oversimplification of the situation. For example, the severity of preoperative coagulation test abnormalities do not predict intraoperative blood loss, nor does the routine correction of abnormal coagulation tests with blood products reduce intraoperative blood loss (and may in fact increase it). 27 Reduced levels of clotting factor, as reflected by prolongation of the PT/INR and APTT, are most likely somewhat offset by decreased levels of natural anticoagulant factors, reduced levels of profibrinolytics, and elevations in von Willebrand factor levels. 27 Thus, the coagulation system in patients with severe liver disease may be more “balanced” than traditional tests of coagulation suggest. However, with overall reduced circulating levels of both prothrombotic and antithrombotic factors, the coagulation system is less robust, and liver failure patients may be prone to both abnormal bleeding and abnormal thrombosis/procoagulation concurrently. 27
Fibrinogen structure and function is abnormal in severe liver disease. 28 Low levels of factor VIII reduce fibrin polymerization, whereas an enlarged vascular endothelial area may increase activation of tissue plasminogen activator, leading to increased fibrinolysis. 28
Thromboembolic phenomena are observed in patients with liver failure, even in the presence of prolonged PT/INR and APTT times. This may be caused in part by abnormal function of the vascular endothelium. 27
The Gastrointestinal System
Portal hypertension from cirrhosis causes esophageal varices and portal gastropathy. Esophageal varices are found in about 50% of patients with cirrhosis at the time of diagnosis. 29 The risk of upper-gastrointestinal bleeding and subsequent pulmonary aspiration should be considered in all patients presenting for liver transplant. Patients may be treated with β-blockers to reduce the risks of esophageal bleeding. 29
Portal hypertension leads to ascites, which is usually managed medically by dietary sodium restriction and diuretic use. Paracentesis and intravenous infusion of albumin is used in more severe cases. 29
Chronic hepatic failure often causes anorexia and malnourishment. Patients may have significant hypoalbuminemia. This affects the intravascular oncotic pressure of these patients and aggravates ascites and peripheral edema. It may have a variable effect on the pharmacokinetics of drugs administered intravenously. It seems reasonable to use 4% to 5% albumin as a colloid solution in hypoalbuminemic liver transplant patients.
Other Considerations
Patients with cholestatic liver disease such as primary biliary cirrhosis may have intense pruritis and skin trauma from itching. Patients with liver failure secondary to hepatitis B or C pose a risk to operating room personnel from needle-stick injuries or other body fluid contamination. Obviously, universal precautions, including gloves and eye protection, are essential, and staff should ensure that their immunization status is up to date. End-stage liver disease patients are prone to viral and bacterial infections, and posttransplantation, this is compounded by the introduction of immunosuppressant medications. This obviously requires the highest standards of hand washing and appropriate aseptic technique for all patient contact and procedures.
Preoperative Assessment
The anesthesiologist caring for the liver transplant recipient must be prepared to manage complex, prolonged surgery; hemodynamic instability; massive blood loss; complex metabolic and electrolyte disorders; coagulopathy; and multiple organ failure. End-stage liver disease affects almost all organ systems, and many of the pathologies that cause liver failure themselves cause multiorgan system disease. Additionally, pathology identified preoperatively in the potential liver transplant candidate may make the transplant procedure high risk or inappropriate.
The liver transplant operation places significant strain on the physiological reserves of the patient through events such as hemorrhage, inferior vena cava (IVC) clamping, and graft reperfusion. Because of the time pressure related to organ procurement and minimizing graft ischemia, transplant procedures often take place outside daylight hours when staffing levels are low, and assistance can be limited.
Comorbid patients fare poorly both in the short and long term after liver transplantation. 10 With a limited donor pool, there is an ethical imperative that compels us to list only those patients who we believe will do well with liver transplantation.
Because of these concerns, a high-quality preoperative assessment of the potential liver transplant recipient is required. Many centers use a multidisciplinary approach, where patients are seen by hepatologists, surgeons, anesthesiologists, specialty nurses, psychologists, transplant coordinators, and others.
Baseline Investigations
It is appropriate that the patient has baseline screening investigations performed. These are often performed and the results assessed before the patient is proposed by the screening hepatologist as a liver transplant candidate. Routine testing of interest to the anesthesiologist may include the following:
complete blood count;
urea, creatinine, and electrolytes; liver function studies, including albumin and transaminases;
coagulation studies, including PTT, INR;
virology studies, including hepatitis A, B, C, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, HIV, varicella zoster virus;
blood group and antibody screening;
arterial blood gas, if oxygen saturations are low;
electrocardiogram;
Chest X-Ray: Posteroanterior and lateral
transthoracic echocardiogram, including estimation of pulmonary artery pressures; and
pulmonary function studies in smokers or those with a history of pulmonary disease.
Specialized Investigations
Additional investigations are typically undertaken at the discretion of the preoperative assessment physician, although many programs use protocols or guidelines to guide practice. In patients with questionable cardiorespiratory reserve, some form of exercise testing is useful. Many liver transplant candidates are unable to exercise adequately because of ascites, deconditioning, encephalopathy, or decreased cardiorespiratory reserve. Many liver transplant candidates are treated with β-blocker therapy to reduce the risk of variceal hemorrhage, and stopping this treatment may place the patient at risk of life-threatening gastrointestinal bleeding. 30
Assessment of prospective liver transplant candidates for the presence of occult coronary atheroma is a growing area of interest. Among patients surviving for 1 year following liver transplant, cardiovascular disease accounts for the majority of non-graft-related deaths. 31 This has implications for the anesthesiologist with regard to the hemodynamic stresses intraoperatively, for preoperative optimization of patients, and in terms of recipient selection for the limited pool of graft organs. The American Association for the Study of Liver Diseases has published a pathway for assessment of patients for potential liver transplantation. 20 The recommendation of the group is that patients older than 50, those with a clinical or family history of heart disease, or those with diabetes should undergo evaluation for CAD with dobutamine stress echocardiography. 20 However, more recent publications have suggested that myocardial perfusion scans such as single-photon emission computed tomography technetium-99 sestamibi scans have a very high sensitivity (100%) in predicting severe CAD, albeit with a relatively poor specificity. 32 Unfortunately, the investigation and management of such patients is complicated because the “oxygen supply versus demand” understanding of flow-restricting coronary lesions may not be as applicable in predicting outcome in transplant recipients as it is in cardiology and vascular surgery. A recent study showed that noncritical but widespread/multivessel coronary disease is more predictive of 1-year mortality, hospital length of stay, and postoperative vasopressor requirement than the presence of a discrete, flow-limiting lesion in liver transplant patients. 11 A possible explanation for this finding could be that postoperative immunosuppression may accelerate the process of coronary atheroma formation. 33
There is no consensus on the best approach to management of the potential liver transplant candidate who is found to have CAD on preoperative assessment. Simultaneous coronary artery bypass grafting is certainly possible at the time of liver transplantation, although outcome data are limited to case reports and small series. 34 A recent series of 16 patients with CAD showed that percutaneous treatment with angioplasty or stenting to coronary lesions to prepare patients for transplant surgery is feasible and safe. 35 Potential issues with this approach include the management of arterial puncture sites in patients with bleeding tendency and thrombocytopenia, vascular contrast administration in the setting of compromised renal function, and the need for dual antiplatelet therapy in patients with potential bleeding sites, including esophageal varices. Computed tomography angiography of coronary arteries is an imaging technique that is noninvasive and has future promise for the preoperative assessment of liver transplant patients; however, experience with the technique is limited. 36
Transthoracic echocardiography is a highly sensitive tool for diagnosing pulmonary hypertension in liver transplant candidates. 19 If the Doppler-derived estimate of pulmonary pressures is elevated, right-heart catheterization should be undertaken. 19 Right-heart catheterization allows assessment of pulmonary vascular resistance and rules out the syndrome of portopulmonary hypertension. These patients need to have cardiology consultation to assess if medical therapy for their pulmonary vasoconstriction is appropriate and the risks versus benefits of proceeding to liver transplantation. 19
Patients with significant dyspnea or hypoxemia need to be assessed for the presence of hepatopulmonary syndrome. In these patients, pulmonary function tests and chest radiographs are often normal. 19 Transthoracic echocardiography using agitated saline (the “bubble test”) is a sensitive and noninvasive option for diagnosis. In individuals with abnormal vascular shunts in the pulmonary circulation, bubbles from agitated saline injected into a peripheral vein are seen within the left atrium and left ventricle within 3 to 6 cardiac cycles, whereas they are not seen in patients without hepatopulmonary syndrome. 19
In patients with a significant history of smoking, pulmonary function tests are appropriate.
Anesthesia Management of the Liver Transplant Procedure
Across the United States, there is significant variability between the size of centers performing liver transplant surgery. In some complex surgical procedures, a link has been made between an increasing volume of cases performed and better outcomes. 37 There are data to suggest that this trend is seen in liver transplantation too, although there are low-volume centers that produce outcomes that rival the largest centers, and many confounders are possible. 37
The conduct of anesthesia for liver transplant varies widely between institutions. It is unclear if any specific approach to, or technique for, anesthesia for liver transplant affects outcome. A key principle is clear communication between members of the nursing, surgical, anesthesia, and perfusion teams. The liver transplant operation lends itself to description in 5 phases: preoperative care and consent, induction and monitoring, the preanhepatic phase, the anhepatic phase, and reperfusion and wound closure phases. These phases will now be discussed in outline.
Preoperative Care, Consent, and Operative Timing
Chronic liver failure patients who are listed for transplant should undergo a full consent process for surgery and anesthesia during the initial preassessment phase. Once an appropriate liver graft becomes available, the patient is contacted urgently, admitted to hospital as soon as possible, and is met and reassessed by surgical, hepatology, and anesthesiology staff for interim changes in clinical presentation, such as fasting status, recent intercurrent illness, and any recent changes in health, such as encephalopathy, gastroesophageal bleeding, or spontaneous bacterial peritonitis.
Patients with severe liver disease may need to be managed preoperatively in the intensive care unit. Those patients with fulminant hepatic failure (see later) will typically be intubated and ventilated, and anesthesia for surgery will involve an extension of neuro-oriented intensive care into the operating room.
Induction and Monitoring
It is usually appropriate to avoid sedative premedication, because patients with liver disease, especially if encephalopathic, are very sensitive to the effects of sedative medications, in general, and benzodiazepines in particular. Sedation of such patients requires close monitoring and supplemental oxygen and may pose an aspiration risk.
The operating room is warmed, and appropriate preoperative surgical checklists are completed. Blood products are brought to the operating room and checked. Standard monitoring would include pulse oximetry, noninvasive blood pressure, and 5-lead EKG monitoring, with specific care taken to secure the oximetry and EKG leads, given the long expected operative time and significant blood and ascites soaking through drapes. Additionally, a forehead bispectral index (BIS) monitoring strip (BIS, Covidien, Mansfield, MA) can be placed preinduction and may allow easier titration of anesthetic depth.
Appropriate intravenous access is placed, with close care given to aseptic technique. A radial arterial cannula is placed using local anesthesia.
An example of drugs for induction of anesthesia would include a combination of benzodiazepine (eg, midazolam; 0.1 mg/kg to a maximum of 10 mg), rapid-acting opioid (eg, fentanyl; approximately 1-5 µg/kg), and propofol (0.3-1 mg/kg). Paralysis may be obtained with a nondepolarizing muscle relaxant such as rocuronium (1-1.5 mg/kg). Concerns exist around the impaired metabolism of aminosteroid muscle relaxants in patients with significantly impaired liver function. 38 It is our experience with rocuronium that prolonged muscle relaxation at the conclusion of surgery is seldom a problem in the presence of a functioning liver graft and that the stable hemodynamics seen with aminosteroid muscle relaxant use are beneficial. Some authors have suggested that impaired metabolism of rocuronium is a useful early sign of primary graft nonfunction. 38
Induction of anesthesia should be undertaken with a rapid-sequence induction, using succinylcholine and cricoid pressure if the patient is unfasted, suffers from or is at high risk for gastroesophageal bleeding, or has a history that suggests impaired gastric emptying. In the absence of these symptoms, a high-dose nondepolarizing muscle relaxant is appropriate and gives similar time of onset to paralysis.
After intubation, anesthesia may be maintained with inhalational anesthesia (isoflurane, sevoflurane, or desflurane at 0.2-1.0 age-adjusted MAC [minimum alveolar concentration] equivalents, titrated to hemodynamics and possibly BIS). It has been suggested that isoflurane offers advantages over sevoflurane and desflurane in terms of its effects on splanchnic blood flow; however, the evidence supporting this assertion is weak. 39 Paralysis is titrated to neuromuscular function by the use of a peripheral nerve stimulator. Some centers use infusions of muscle relaxant and narcotic during surgery.
After discussion with the surgical team an orogastric or nasogastric tube is often inserted, with attention paid to the coagulation status of the patient and the risk of severe epistaxis.
Large-bore intravenous access and invasive monitors are required for the procedure. The specific types of lines placed are less important than the confidence that the anesthesiologist has in his/her ability to transfuse large volumes of colloid and blood products through them, should significant bleeding ensue. In the authors’ institution, “volume” intravenous access includes at least one 14-g intravenous cannula and an ultrasound-guided 8.5 French pulmonary artery catheter introducer sheath, which is usually placed in the right internal jugular vein. If there is anticipated need for venovenous bypass, the right neck is preserved for the venous inflow cannula and the line placed in the left internal jugular vein.
Many centers place a pulmonary artery catheter and complete a set of cardiac output measurements using the thermodilution technique at the start of the case. This practice is variable around the world, with a greater preference for pulmonary artery catheter placement in North America versus European centers. 40 The placement of pulmonary artery catheters allows early identification of patients with undiagnosed pulmonary hypertension. Additionally, the real-time information on cardiac output and volume status that can be gained from the pulmonary artery catheter makes it a useful tool. Pulmonary artery occlusion pressure estimation of left atrial pressure is often avoided because of the risk of pulmonary artery rupture.
Transesophageal echocardiography (TEE) has been only sporadically used as a cardiovascular monitor during orthotopic liver transplant. This is most likely because of concerns about the risk of provoking hemorrhage from the gastric or esophageal mucosa in patients with portal hypertension and impaired coagulation. Despite these concerns, in some centers, its use is routine. 41 Benefits of TEE include the rich, continuous real-time information gained about volume status and cardiac function. In a recent retrospective study of TEE in 396 liver transplant recipients, of whom 287 had known esophageal varices, there was only 1 serious case of gastrointestinal bleeding (a patient who then died postoperatively from primary graft dysfunction and multiorgan failure), giving a complication rate of 0.3%. 41 The authors argued that TEE represents a relatively safe method of cardiac monitoring in this group. Obvious arguments against the routine use of TEE would be the (as-yet) unquantified value of the information gained from the monitor in the setting of orthotopic liver transplant, the equipment costs, anesthesiologist training and skill-maintenance costs, and associated staffing implications.
Meticulous attention needs to be paid to positioning the patient for what can be a prolonged surgery and attention paid to pressure from, for example, surgical retraction frames.
Some form of rapid transfusion device is mandatory for liver transplant surgery. Typically, broad-spectrum antibiotics and appropriate immunosuppressive agents such as methylprednisolone are administered according to institutional protocol. Attention to meticulous hand washing and scrupulous aseptic technique is vital when dealing with these immunosuppressed and vulnerable patients.
Preanhepatic and Dissection Phase
This phase begins with surgical incision and ends with identification and clamping of the blood vessels into and out of the diseased liver—namely, the suprahepatic and infrahepatic IVC, the hepatic artery, and hepatic portal vein. 39 During this phase of surgery, ascites is drained, adhesions are taken down, the vascular and biliary structures are identified, and the diseased liver mobilized. There is the possibility of significant volume shifts with drainage of abdominal ascites. 39 During this phase, management involves cautious intravascular volume loading with colloid such as 5% albumin solution, aiming for a low central venous pressure of around 5 cm H2O. Blood loss during this phase of surgery may be significant. Previous abdominal surgery (including hepatic resection or liver transplant) or previous intra-abdominal sepsis, including spontaneous bacterial peritonitis, may make this phase of surgery more difficult and bleeding more significant. Administration of blood products may be guided by clinical findings or by monitors of coagulation, such as laboratory PTT, INR, and fibrinogen or bedside tests such as thromboelastography and the clinical picture of coagulation function within the surgical field. Administration of volume should be a balance between maintaining low central venous pressure in the interests of restricting surgical blood loss and maintaining adequate filling pressure and preload to the heart in anticipation of the significant drop in preload associated with clamping of the IVC and hepatic portal vein.
Vasopressin is a potent vasoconstrictor, which has beneficial effects on the dilated splanchnic bed in patients with portal hypertension and ascites. As many patients with end-stage liver disease are vasodilated and relatively hypotensive on arrival to the operating room, it is often necessary to commence a vasoconstrictor infusion with induction to offset the effects of anesthesia. A vasopressin infusion can be used for this purpose in such patients during the anhepatic phase with the aim of optimizing organ perfusion, and the splanchnic vasoconstriction may decrease bleeding from surgical trauma to abnormally dilated intra-abdominal veins.
It is important to correct systemic hypocalcemia and hypomagnesemia with a slow intravenous infusion of calcium chloride and magnesium sulfate. Frequent blood testing allows maintenance of stable hemoglobin, clotting, electrolyte, and serum glucose parameters. It is important to aim not to correct clotting indices per se but rather to be also guided by clinical assessment of blood coagulation within the surgical field.
Anhepatic Phase
This phase begins with occlusion of blood supply to the liver and ends with reperfusion of the graft. 39 This phase typically takes approximately 1 to 1.5 hours. The main hemodynamic consideration of this phase of the surgery is the effect of clamping of the IVC with a resultant decrease of up to 50% in venous return to the heart. 39
Conventional and “piggyback” liver transplant techniques
There are 2 major approaches to the removal of the diseased liver. Historically, the recipient hepatectomy involved infrahepatic and suprahepatic IVC cross-clamps. A more recent surgical development is the use of an IVC-sparing technique, called the piggyback technique. 42 This method uses only partial or side clamping of the IVC, with preservation of some caval flow. This technique causes less hemodynamic compromise and leads to shortened operative and warm ischemia times, reduced red blood cell and blood product use, and similar graft function and survival outcomes. 43 The piggyback technique has become the dominant technique now used worldwide. 43
Venovenous bypass
From the 1960s, some centers have used a circuit to bypass the IVC cross-clamp and return blood from the portal and lower-body venous system to the superior vena cava. 44 Typical systems involve cannulae placed into the femoral vein (by surgical cut down or Seldinger technique), the portal vein, and the axillary or internal jugular vein. Heparin-bonded circuits are utilized, which do not require systemic anticoagulation, typically using a centrifugal pump, meaning that flow is pressure dependent in the circuit. 45 Benefits initially seen with the introduction of the technique were improved hemodynamic stability in the presence of the caval cross-clamp, better renal and intestinal perfusion, and decreased blood transfusion. 44 Complications include seroma and lymphocele formation, wound infection, thrombosis, gas embolism, nerve injury, hypothermia, coagulation defects and fibrinolysis as a result of blood exposure to tubing, the need for trained perfusion personnel, cost, and increased bleeding related to vessel cannulation. 44 There continues to be debate in the literature as to the relative overall balance between benefits and downsides.
The preserved flow through the partially patent IVC when the piggyback liver transplant technique is used permits adequate venous return, such that many centers do not use venovenous bypass in any circumstance or only after a trial of hepatic vascular inflow clamping reveals profound hemodynamic instability. 44 A reasonable approach is to consider the use of venovenous bypass only if trial clamping of the IVC causes profound hypotension associated with a dramatically reduced cardiac index, which does not respond to inotropes and volume loading, or if anatomy or surgical expertise precludes the piggyback approach. A flow rate of 2 to 3 L/min is targeted, and depending on preexisting coagulopathy, a small dose of heparin may be given to reduce the risk of in-circuit clot formation.
With the exclusion of the native liver from the patient’s circulation, there are profound effects on the patient’s metabolic state. The most significant change during the anhepatic phase is the loss of the lactate-metabolizing capacity of the liver and a rise in plasma lactate and decrease in plasma pH. 46 This lactic acidosis is exacerbated when the graft liver is reperfused, and thus, many practitioners choose to treat the acidosis during the anhepatic phase to reduce the risk of severe acidosis with reperfusion. 46 In practice, a good approach is to use bolus doses or an infusion of sodium bicarbonate solution as guided arterial blood gas measurements. An infusion rate of 100 cc/h of 8.4% solution is a suitable technique, titrated to arterial pH. Possible concerns about this treatment include the failure of sodium bicarbonate to correct intracellular acidosis and the significant load of sodium administered, which risks overrapid correction of preexisting hyponatremia. 46 It has been suggested that dichloroacetate solution may be a better agent to treat the lactic acidosis of the anhepatic phase. 46
In patients with profound preoperative liver failure or if the anhepatic phase is prolonged, it is appropriate to monitor and treat plasma glucose. If large volumes of blood products are transfused during the anhepatic phase, the reduced capacity of the body to metabolize citrate in the absence of the liver can lead to citrate-associated hypocalcemia. 28 Particular care should therefore be paid to plasma ionized calcium levels during the anhepatic phase to avoid the risk of reduced vascular tone and compromised myocardial contractility. 28
Some authors suggest that intraoperative continuous renal replacement therapy can stabilize electrolyte and acid-base status when other therapies appear to fail. 24 A possible additional benefit may be the ability of renal replacement therapy to reduce cytokine levels following reperfusion of the graft. 24 Downsides include the cost of personnel and equipment and potential difficulties with continuous renal replacement filters clotting if heparin is avoided. 24
Graft Reperfusion
This phase of the procedure commences with reperfusion of the liver graft (usually after completion of the vena cava and portal vein anastomoses) and ends with skin closure and transfer of the patient to the recovery area or ICU. During this phase of surgery, the liver graft is reperfused with the recipient’s blood via both hepatic portal veins and hepatic arteries, and biliary anastomoses are formed. If the recipient’s biliary system has unfavorable anatomy or is diseased, the graft biliary system may require anastomosis to the recipient small bowel, adding significantly to the operating time.
Postreperfusion syndrome
Postreperfusion syndrome is the most significant anesthetic concern during the reperfusion phase. This syndrome consists of severe cardiovascular dysfunction with decreased cardiac output, severe systemic hypotension, bradyarrythmia, asystole, raised pulmonary artery pressure, and raised pulmonary capillary wedge pressure and central venous pressure. 47 It is observed in the first minutes following reperfusion of the liver graft, and if not managed actively, fatal cardiac arrest can ensue. The formal definition of the syndrome has been refined to include a requirement for the mean arterial pressure to drop at least 30% for a period of at least 1 minute within 5 minutes of reperfusion. 45 EKG changes are also often seen. 45 The mechanisms underlying postreperfusion syndrome are complex. 48 It is likely that products of metabolism from the ischemic liver graft, including vasoactive substances such as interleukin 6, tumor necrosis factor α, potassium and hydrogen ions, and possibly emboli are released into the recipient’s bloodstream and directly into the right heart. 48 Additional effects are seen with the solute release associated with various graft-preservation solutions, such as University of Wisconsin solution, which contains a significant potassium load.
Postreperfusion syndrome has proven difficult to predict, with only increasing age of the liver graft donor being a strongly predictive factor. 47 Associations have been made between the occurrence of postreperfusion syndrome and poor outcome measures such as postoperative renal function and postoperative survival. 48 It is not clear if these associations are causative.
Various methods are used in attempts to modify the severity of this syndrome with variable effects, including flushing the graft with cold saline or autologous blood, sequential or partial unclamping of hepatic graft outflow, and anticipatory use of various antihistamine agents, vasopressors, calcium, and bicarbonate. The authors’ approach is to communicate closely with the surgical team regarding the timing of reperfusion, closely monitor the hemodynamics of the patient at the time of graft outflow unclamping, and pretreatment of the patient with the antihistamine agents ranitidine and diphenhydramine in the 15 minutes prior to reperfusion. Hemodynamic perturbations are treated with vasopressor agents, including cautious bolus doses of phenylephrine, norepinephrine, and epinephrine. Calcium chloride and sodium bicarbonate are often also administered, guided by arterial blood gas results. Methylene blue has been used as a “last-resort” treatment for catecholamine-resistant vasoplegia postcardiopulmonary bypass. At a dose of 1 to 2 mg/kg, it has been reported to have useful effects in the treatment of severe postreperfusion syndrome that is resistant to other treatments; this effect is most likely mediated by inhibition of guanylate cyclase in vascular and cardiac tissue. 49
During the reperfusion phase of the liver transplant operation, it is vital that the anesthesiologist respond actively to physiological changes in the patient in order to optimize the conditions for graft survival. Key among these is maintenance of appropriate perfusion pressure to the new graft and avoidance of high central venous pressures, which may contribute to graft hepatic venous congestion. The surgeon is often able to advise the anesthesiologist at this stage about the venous congestion of the graft and its color and may request lowering of the central venous pressure to optimize this situation. The instigation of a diuresis at this stage of the procedure, typically with mannitol and furosemide, may be appropriate if there is graft venous engorgement. Additionally, venous vasodilators such as glyceryl trinitrate can be utilized, provided blood pressure does not drop to unacceptable levels. There is significant information available at this point regarding function of the new graft. Surgical signs such as the production of bile and a “healthy color” of the graft may be noted by the surgeons. Additionally, the thermal load absorbed by the body of the reperfusion of an ice-cold 1- to 1.5-kg organ is significant. 45 It is expected that the recipient’s core temperature (measured, for example, by a temperature probe on the pulmonary artery catheter) will drop approximately 0.5°C to 1°C in the minutes following reperfusion. A relatively rapid increase in core temperature of the recipient following this initial dip can be regarded as an important sign of exothermic cellular metabolism and function of the graft. Additionally, improvement in acid-base status and stable glucose levels are reassuring signs of graft function. If the surgery has been prolonged, additional antibiotics may be administered according to institutional protocol.
Postoperative Care
By definition, liver transplant recipients have at least single-organ (and often multiple-organ) failure and thus can be categorized as critically ill. 50 Most liver transplant recipients are managed in the intensive care unit postoperatively. This allows close monitoring of the patient’s hemodynamics, respiratory function, metabolic and coagulation status, and renal function. Additionally, intensive care of liver transplant recipients requires a focus on, and consideration of, the perfusion and function of the graft. 51 The intensive care stay following liver transplantation accounts for a significant proportion of the cost of the overall procedure.
Some investigators have recently challenged the historical view that all liver transplant recipients benefit from a period of ventilation and stabilization in the intensive care unit after transplant. 52 It has been suggested that mechanical ventilation, especially with positive end-expiratory pressure, increases intra-abdominal venous pressures, which in turn leads to reduced graft venous outflow and venous congestion at the stage at which the newly transplanted graft is the most vulnerable. 1 Some large centers have instigated policies whereby the majority of liver transplant recipients are extubated either in the operating room at the end of the procedure or in the postanesthesia care unit soon after. 1 Some centers have gone even further, with liver transplant recipients being discharged from the postanesthesia care unit directly to a closely monitored surgical ward, bypassing the intensive care unit altogether. 52 Both the practice of extubation of the recipient by the anesthesiologist soon after wound closure and the bypassing of the intensive care unit have been referred to as fast-tracking. 52 Both techniques require selection of patients who are expected to recover rapidly following their transplant, usually with isolated liver dysfunction and relatively low preoperative MELD scores. 52 It is unclear if these practices improve outcome or indeed reduce overall costs, and although perhaps promising from an economic perspective, cannot yet be considered routine posttransplant medical care.
Special Considerations
Fulminant Hepatic Failure
Acute liver failure is defined as acute injury to the liver accompanied by hepatic encephalopathy, usually in the setting of previously normal liver function or at least well-compensated liver disease. 53 It is an uncommon but devastating complication of acute insult to the liver and carries a mortality risk of between 40% and 80%. 53 If the onset of encephalopathy is particularly rapid (less than 2 weeks), the syndrome is described as fulminant hepatic failure. 53 The common causes of fulminant hepatic failure include viral hepatitis, acetaminophen overdose, and other drugs/toxins. 53 From the perspective of the transplant anesthesiologist, primary graft nonfunction of a recently transplanted liver or other cause of rapid-onset graft dysfunction, for example, hepatic artery thrombosis, presents a very similar clinical picture.
Although it is common for patients with chronic hepatic disease to present for liver transplant with varying degrees of hepatic encephalopathy, patients with acute liver failure are unusual in the severity of the neurological manifestation of their liver dysfunction. Additionally, encephalopathy in acute liver failure is often accompanied by cerebral edema and raised intracranial pressure. 53 Cerebral edema develops in 70% to 80% of patients with coma in fulminant hepatic failure and is a major cause of death. 53 Management instituted in the intensive care unit may include various types of intracranial pressure monitors, hyperventilation, mannitol or hypertonic saline osmotherapy, cooling, head-up positioning, and muscle paralysis, with close attention to maintenance of cerebral perfusion. It is important to aim for a cerebral perfusion pressure of at least 50 to 60 mm Hg in these patients to preserve cerebral oxygenation.
Various prognostic tools are used to distinguish between patients with acute liver failure who will benefit from transplantation and those who can be expected to recover spontaneously, including the King’s College Hospital criteria. 39 This system uses the etiology of the acute liver failure, arterial blood pH, PT/INR, serum creatinine, age, speed of onset and severity of encephalopathy, and serum bilirubin to predict patients likely to die without a transplant. 54 Patients subsequently selected for transplantation will be allocated high priority for donor organs, and thus, the period of time from consideration of transplant to surgery may be short. This demands close coordination between anesthesiologists, surgeons, hepatologists, intensivists, and transplant program coordinators to ensure that the patient is indeed an appropriate transplant candidate and has had appropriate assessment and investigations undertaken, without unduly delaying the procedure.
Coagulopathy is typically worse in fulminant hepatic failure patients compared with coagulopathy in those with chronic liver disease. Aggressive treatment with appropriate blood products may be required. Metabolic abnormalities are common in patients with fulminant hepatic failure and include hypoglycemia, which is seen in 45% of patients. 53 Other commonly seen abnormalities include lactic acidosis, hyponatremia, hypokalemia, and renal failure.
The management of the anhepatic phase of patients with fulminant hepatic failure is often more demanding than in patients with chronic liver disease. It is thought that the absence of intra-abdominal venous collaterals in patients with acute rather than chronic hepatic failure means that partial or total occlusion of the IVC with surgical clamping causes a more profound reduction in venous return and cardiac output. Additionally, the effect of hemodynamic and electrolyte disturbances on cerebral perfusion and intracranial pressure must be minimized.
Live Donor Liver Transplantation
The liver has remarkable powers of regeneration. Anatomically, it can be divided into 8 discrete segments, each with independent vascular inflow and outflow anatomy and biliary drainage. 55 Combined, these 2 attributes enabled the first live donor liver transplant to take place in 1987 in Australia. 55 The procedure typically uses a left-lateral segment, left lobe, or right lobe of liver from a healthy donor as the graft for the recipient. There are many advantages of this concept: it optimizes timing of transplantation and adds a liver graft to the pool of available organs. 55 There is minimal preservation time because the graft is usually removed in an operating room at close proximity to the recipient, with the surgical times overlapping. The donor liver is usually very healthy and has never been subjected to the adverse physiological conditions present in the brain-dead donor. Because the use of live donor grafts does not reduce the size of the deceased-donor graft pool, patients are often accepted for live donor grafts where they would not be listed for deceased-donor transplant. 55 Live-donor liver graft donors often report strongly positive attitudes regarding the procedure postoperatively because they feel that they have literally given another person, often a friend or family, a gift of life. 55
Live-donor liver transplantation also, however, has many disadvantages. The most obvious are the ethical issues of placing an otherwise healthy person at risk of morbidity (0%-67%) and death (0.1%-0.5%). 55 The morbidity of the donor operation is directly related to the size of the graft resection and includes wound infections, pleural effusions, bile leaks and duct strictures, bleeding, deep venous thrombosis, pulmonary embolism, urinary tract infection, and pneumonia. 55 Both the donor and recipient operations are technically demanding procedures. The donor surgery is difficult because unlike liver resection for pathological causes, great care must be taken in handling the excised graft to preserve the tissue, vasculature, and biliary system. 55 Likewise, the recipient surgery is considered more demanding than a deceased-donor procedure because of the need to match a relatively small graft with potentially damaged vessels and bile ducts to the much larger recipient vessels and bile duct. 55
A major consideration of the procedure is size matching between donor and recipient: too large a graft resection places the donor at unnecessary risk, whereas too small a graft places the recipient at risk of graft failure or small-for-size syndrome. This is a syndrome where there is impaired synthetic function, cholestasis, and raised liver enzymes, probably as a result of relative overperfusion of the graft following removal of a large diseased liver and replacement with a smaller, partial liver graft. 55
Coagulation Management, Antifibrinolytic Therapy, and Cell Salvage
Liver transplantation surgery in its infancy was characterized by massive volume blood loss and high-volume transfusion of blood products. 39 More recently, rates of blood product use in liver transplant have been reported to vary from 20% to 96%, with average doses of red blood cells ranging from 0.5 to 8 units. 56 Blood transfusion during liver transplantation has been associated with a range of adverse patient and graft outcomes. 56
In a large series of 500 consecutive patients undergoing orthotopic liver transplant, the factor most strongly associated with intraoperative transfusion was preoperative hemoglobin concentration. 57 The anesthesiologists targeted a low central venous pressure by restricting fluid therapy, particularly in the early stages of the procedure. There was no relationship between blood loss and variables denoting severity of liver disease such as INR, platelet count, MELD score, bilirubin, or creatinine. 57
During liver transplantation surgery, the coagulation status of the patient, if left untreated, may deteriorate rapidly as a result of dilution, heparin effect, fibrinolysis, excessive clot formation in surgical wounds, hypocalcemia, and hypothermia. 58 Some authors have suggested that point-of-care monitoring of coagulation with systems such as thromboelastography provides an ideal system of monitoring because it can distinguish between clotting problems from deficiency of coagulation factors, low or dysfunctional platelets, hypofibrinogenemia, and fibrinolysis. 58
There is evidence that procoagulant and antifibrinolytic drugs may reduce blood transfusion requirements in liver transplantation. 56 The data addressing these issues is unfortunately of imperfect quality. A recent meta-analysis by the Cochrane Collaboration of 33 trials involving 1913 patients reviewed the use of drug treatments, including antifibrinolytics (aprotinin, tranexamic acid, and epsilon aminocaproic acid), procoagulants (antithrombin 3, recombinant factor VIIa, estrogen, prostaglandin, and epinephrine), blood substitutes, thromboelastography, and low central venous pressure–directed management. 59 The authors’ conclusion was that the use of aprotinin, recombinant factor VIIa, and thromboelastography may potentially reduce blood loss and transfusion requirements during liver transplant surgery but that further studies with well-designed trials were required before stronger recommendations could be made. 59 There are significant limitations associated with these conclusions, no matter the statistical basis on which they are made: aprotinin is no longer commercially available in the United States, whereas the use of both recombinant factor VIIa and thromboelastography are associated with significant expense. Local practice, cost, and surgical experience are also relevant to decision making around coagulation management in liver transplantation.
Cell salvage techniques use blood from the surgical field, which would traditionally have been discarded, as a source of red blood cells. This blood is washed and filtered before being reinfused into the patient. The obvious benefit of this technique is a reduced reliance on banked, allogeneic blood from donors. Potential downsides include the need for expensive, relatively complex equipment and trained personnel to operate it and concerns regarding reinfusion of contaminants such as bowel or peritoneal microorganisms, malignant cells, fat, denatured protein, or inflammatory mediators. 60 Additionally, the infused product consists of erythrocytes resuspended in saline and thus contains no clotting factors or platelets. The suction in cell salvage systems is typically limited to avoid mechanical trauma to the erythrocytes and thus may be inadequate to remove rapidly collecting blood from the surgical field. Finally, the process of collection, washing, resuspension, filtering, and reinfusion takes many minutes and is thus not suitable for correction of rapidly developing hypovolemia.
Summary
Anesthesia for liver transplantation surgery is complex and demanding. The transplant anesthesiologist must understand that end-stage liver disease is manifest not only in disturbances of the function of the liver but also in derangements of other organs such as the cardiac, respiratory, renal, neurological, hematological, and gastrointestinal systems. An understanding of these problems is crucial to the safe care of these patients.
A multidisciplinary preoperative assessment is required before liver transplant surgery, and anesthesia assessment is a vital part of this process. One of the purposes of such assessment is to identify patients who may not be appropriate candidates for transplant or who need further treatment before coming to surgery. The assessment should focus on the cardiac and respiratory systems, and the use of investigations to assess these organs needs to be cost-effective and evidence based.
The liver transplant procedure itself can be divided into preanhepatic, anhepatic, and reperfusion phases, and there are important anesthesia considerations at each step. Key skills required of the anesthesiologist are the technical expertise required to place appropriate monitoring and transfusion lines; management of hemorrhage; monitoring and treatment of electrolyte and metabolic disturbances; treatment of sequelae of reperfusion, including reperfusion syndrome; and monitoring and treatment of coagulopathy.
Evolving areas within the specialty include the role of point-of-care coagulation monitors such as thromboelastography, the use of cell-salvage equipment, the use of intraoperative TEE, and the fast tracking of patients following liver transplantation.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.