Candidate Selection

Optimal candidates are those for whom the risk of surgery is far outweighed by the potential improvement in their quality of life. Furthermore, the risk of recurrence of the primary disease should be low.^7,8 Not surprisingly, those who are at the highest risk with surgery also achieve the greatest gains when they survive. Unfortunately, such patients have a higher mortality and require significantly greater resources, particularly intensive care and rehabilitation. There are few absolute contraindications to OLTX. However, factors have been identified that significantly increase the risk and should be recognized as relative contraindications (Table 197-1). From the surgical perspective, prior right upper quadrant abdominal surgery, particularly biliary reconstruction, results in a technically more difficult procedure. Patients who are sicker with higher MELD scores or U.S. United Network Organ Sharing (UNOS) Status,^1,9 particularly those with fulminant hepatic failure, fare worse. Patients with higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores who are in the intensive care unit (ICU) and require mechanical ventilation or hemodialysis have lower survival. Of course, medical therapy in such circumstances is even less successful, and APACHE II models hospital outcome well. However, after transplantation, mortality does not rise linearly as a function of recipient acuity. Patients with high APACHE II scores have a higher post-OLTX mortality than recipients with very low preoperative scores. However, there is a plateau of approximately 25% for recipients with preoperative APACHE II scores greater than 20 (Figure 197-1). This observation suggests that carefully selected but very ill patients benefit from OLTX.

TABLE 197-1 Contraindications to Liver Transplantation

AIDS, acquired immunodeficiency syndrome; ESLD, end-stage liver disease; HIV, human immunodeficiency virus; mPAP, mean pulmonary artery pressure; RV, right ventricular.

Figure 197-1 APACHE II model applied to patients with end-stage liver disease (ESLD) who require ICU admission: 1381 patients did not undergo liver transplantation during that hospitalization (No OLTX), and 489 patients were transplanted during that hospitalization (OLTX). A, Distribution of scores in patients who were not transplanted. B, Distribution of scores in those transplanted. C, Mortality by APACHE II score in those not transplanted. D, Mortality by APACHE II score in those transplanted. E, Observed mortality as a function of predicted mortality based on APACHE II scores in both the group of patients not transplanted (which tracks the line of identity) and those transplanted.

Patients with cirrhosis and underlying hepatocellular carcinoma are candidates for OLTX if the disease is limited to the liver and the lesions are small, there is no evidence for major intrahepatic venous invasion, and nodal disease is absent. The widely accepted Milan criteria (1 lesion less than 5 cm or 3 lesions each less than 3 cm) have been modified and established as the University of California at San Francisco (UCSF) criteria (1 lesion = 6.5 cm or 3 or fewer nodules with the largest = 4.5 cm and the total tumor diameter = 8 cm without gross vascular invasion); survival is more than 80% for these patients.¹⁰ Extensive radiologic staging of these patients to stratify them into tumor stages is imperative so the risk of postoperative recurrence can be estimated. Patients with biliary tract malignancy such as cholangiocarcinoma have a very high rate of recurrence.^11,12 It seems doubtful that more extensive resection, including the liver, a portion of small bowel, and pancreas, will be more successful in controlling recurrence of these tumors.^13,14 Preoperative chemotherapy and irradiation may improve outcome after liver transplantation and is under investigation.¹⁵

The risk for recurrence of viral hepatitis in the transplanted organ differs for hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), and hepatitis E. HAV is an acute illness that may cause fulminant hepatic failure and does not recur after transplantation. Recurrence of HBV, once a near-universal problem¹⁶ except after transplantation for fulminant HBV, has been greatly reduced by the routine use of hepatitis B immune globulin (HBIG) titrated to levels of anti-HBV surface antigen antibody (HbsAb) and antivirals such as tenofovir and entecavir—associated with less emergence of drug resistance than lamivudine and adefovir.¹⁷ Active HBV replication, documented by the presence of HBV-DNA, must be suppressed with antivirals before surgery.^18–24 For reasons that are unclear, early reports indicated that patients transplanted with HBV fared worse at each postoperative stage than those with other causes of ESLD.²⁵ Some have speculated that this is a systemic disease accounting for both the high rate of reinfection in the absence of prophylaxis and the decreased survival. Hepatitis C presents a more complicated conundrum. Reinfection of the transplanted organ is universal. Currently there is no effective prophylaxis. Clinical progression is highly variable and not predictable. Some patients experience rapid deterioration and graft failure within the first year, but others have little histologic damage several years after liver transplantation. Hepatitis after transplantation may be treated with pegylated recombinant interferon (IFN)-α_2b, and ribavirin, but is variably tolerated. Sustained suppression of HCV at the end of therapy is reported to be approximately 26% at 3 years.²⁵ The effect of targeted immunosuppression, particularly reduced corticosteroid dosage, on recurrence of HCV and progression to fibrosis is under investigation.²⁶

HIV-infected liver transplant recipients tolerate carefully titrated immuno-suppression. Survival after OLTX is only slightly lower for HIV-positive patients than it is for HIV-negative patients,^9,27–29 with post-transplant morbidity and mortality related to recurrence of hepatitis C in co-infected patients.³⁰

Patients with thrombosed portal veins present a formidable surgical challenge. Options include portal endovenectomy or anastomosis of the donor portal vein to the confluence of the superior mesenteric and splenic veins. Patency of the superior mesenteric vein should be demonstrated by ultrasonography or magnetic resonance imaging (MRI) or angiography before surgery. Occlusion of the superior mesenteric vein usually precludes OLT. Although the portal vein may be anastomosed to the recipient inferior vena cava with a proximal caval ligature placed to sustain flow, mesenteric venous hypertension persists, and gastrointestinal (GI) hemorrhage, ascites, and lower-extremity edema remain problematic. Combined hepatic and intestinal transplantation or multivisceral transplantation are alternatives.³¹

Acute liver failure (ALF; known formerly as fulminant hepatic failure [FHF]) is liver failure with encephalopathy that develops in patients without prior liver disease within an 8-week period or less.³² Mortality is high and predictable.³³ Liver transplantation is the only therapeutic option for patients with progressive liver failure, increasing survival at one year from 20% to 75%.^34,35 Such patients are critically ill at the time of transplantation. They require intensive hemodynamic and neurologic monitoring preoperatively, including measurement of intracranial pressure (ICP)^36–40 and cerebral blood flow (CBF). A few patients will improve with supportive care, particularly young patients with acetaminophen intoxication, Amanita poisoning, or hepatitis A. But most experience a deterioration in their conditions. In contrast to patients with chronic liver disease, hepatic encephalopathy is associated with intracranial hypertension, particularly in patients with multiple organ system failure and hyponatremia.^17,41–45 Inadequate cerebral perfusion, cerebral herniation, and brain death preclude OLT.⁴⁶ Progressive arterial vasodilation may result from the failing liver, mesenteric hypertension, infection, pancreatitis, and adrenal insufficiency, with resultant hypotension despite elevated cardiac output. Cardiovascular instability,⁴⁷ atrial and ventricular arrhythmias,⁴⁸ and respiratory insufficiency (acute lung injury/acute respiratory distress syndrome [ALI/ARDS]) are common complications of ALF and substantially increase operative risk. If preoperative support requires greater than 1 µg/kg/min of epinephrine (or equivalent) or positive end-expiratory pressure (PEEP) greater than 12 with FIO₂ above 60%.

Patients with ESLD severe enough to make them eligible for OLT often experience a precipitous deterioration (acute on chronic liver failure, AoCLF) and require admission to the ICU. Common precipitants include infection (particularly pneumonia and spontaneous bacterial peritonitis) and GI bleeding (from esophageal or gastric varices, portal hypertensive gastropathy, or gastric or duodenal ulceration). Although these events herald the impending demise of the patient and intensify the search for a donor organ, they also further compromise the potential recipient and may lead to multiple organ dysfunction syndrome (MODS) and death.

The decision regarding when a patient is “too sick” to undergo OLTX is complex and reflects a balance of recipient acuity (assessed by MELD, APACHE, level of vasopressor, dialytic and ventilatory support), donor risk index, and surgical, anesthesia, and critical care resources available at the time the donor is identified. Comorbidity in the form of extrahepatic disease unrelated to liver failure with estimated 5-year mortality in excess of 50%, extrahepatic malignancy or infection, irreversible neurologic injury, and cardiopulmonary support in excess of that noted above for ALF would preclude OLT in our institution. Liver failure–associated MSOF resolves with restoration of liver function after successful transplantation.

Donor Selection and Operation

Liver allograft function reflects both recipient and donor factors. Although individual donor characteristics such as age, steatosis, hypernatremia, and impaired lidocaine clearance^49,50 have been associated with poor allograft function, a recent study of a large group of patients allowed analysis of donor factors while controlling for recipient-specific characteristics.⁵¹ Deceased donor characteristics which independently predicted an increased risk of graft failure included age, donation after cardiac death (DCD), split or partial grafts, race, height, and cause of death (Table 197-2). Decreased graft survival may also be associated with unique pairings of donor and recipient characteristics. For example, liver function in HCV-positive recipients is worse when the donor is older than 60 years of age.⁵²

Brain death results in marked changes in homeostasis for the donor. Hemodynamic instability is common and may result in part from massive free-water deficits caused by diabetes insipidus. Correction of diabetes insipidus with desmopressin and adequate hemodynamic monitoring and intervention are essential to preserve vital organ function. Anesthesia blunts the response to surgical stimulation. A skilled surgical dissection with rapid identification of the hepatic vessels,⁵³ cannulation and perfusion with University of Wisconsin (UW) solution, and rapid cooling are essential for graft preservation. Acceptable cold ischemia times have dropped. Despite a report of successful graft function after prolonged cold ischemia times of up to 24 hours,⁵⁴ the best outcome is associated with 6 hours or less.

Donation after cardiac death (DCD) results in a graft with an additional warm ischemic insult–a consequence of the hypotension and hypoxemia of that result from with drawal of hemodynamic and respiratory support–until death is pronounced and cannulae can be placed to infuse cold preservative solution. Alternative preservation techniques including less viscid than cold UW solution as well as allograft perfusion with thrombolytics are under investigation.⁵⁵ A significant learning curve attends the successful use of DCD grafts with biliary complications noted by all but lower survival and hepatic arterial thrombosis reported by some⁵⁶ but not all programs.⁵⁷

Living donation is the only option for liver transplantation in many parts of the world. However, in the United States the number of living donor liver transplants is falling from its peak in 2001—constrained by the success of deceased donor liver transplantation, including the falling overall mortality after introduction of MELD for liver allocation and the risks inherent in the donor surgery. In 2009 only 219 liver transplants were from living donors, compared with 6101 from deceased donors.⁵⁸ Evaluation includes confirmation of the emotional relationship between donor and recipient, evaluation of the donor for medical disease, and anatomic compatibility. Liver segment to donor weight ratios of 0.8% to 1% are needed to avoid small-for-size syndrome. However, donation of the right lobe results in increased donor complications. The reader is referred to a recent detailed review.⁵⁹

Recipient Operation

The recipient operation has become a highly refined surgical procedure. Improvements in anesthetic and surgical practice have made evident the importance of the other factors described previously—candidate selection and donor organ quality—in the eventual outcome for the recipient. The surgical procedure may be divided into three stages: hepatectomy, anhepatic phase, and post-reperfusion phase. Each involves special consideration by the anesthesiologist and surgeon.

Monitoring includes pulse oximetry, electrocardiography, and continuous measurement of arterial pressure (often from two vessels) and pulmonary arterial pressure. Maintenance of large-bore central venous catheters (e.g., two 8.5F introducers) and the ability to infuse whole blood at rates as high as 2 L/min with a rapid infusion system are essential to maintain hemodynamic stability during occasional episodes of massive hemorrhage. More extensive monitoring is indicated in selected cases. Right ventricular function may be compromised by the presence of pulmonary hypertension, a complication that can develop acutely during reperfusion.^60–63 Right ventricular ejection fraction and end-diastolic volume are more sensitive guides to cardiac preload than are central venous and pulmonary artery occlusion pressures. These values may be obtained by use of the oximetric pulmonary artery with rapid-response thermistor catheter (Edwards Lifesciences Corp., Irvine, California).¹ However, more robust cardiovascular assessment is provided by intraoperative transesophageal echocardiography. This tool provides a dynamic online picture to the anesthesiologist, allowing him or her to assess the adequacy of resuscitation. In patients with ALF and intracranial hypertension, ICP monitoring is essential. Although CBF measurement in the operating room is difficult, flow can be estimated by the contour of the transcranial Doppler and balance of oxygen supply and demand inferred from the arterial-jugular venous oxygen content difference.⁶⁴ CBF also may be assessed using transcranial Doppler ultrasound to measure the velocity of flow in the middle cerebral artery. Continuous electroencephalography (EEG) and compressed spectral array are under investigation as monitoring techniques in this setting.

A rapid-sequence induction of anesthesia is indicated, as gastric motility is impaired in patients with cirrhosis, and the procedure may be performed before an adequate period of fasting. Anesthesia is often induced with propofol, fentanyl and succinylcholine and maintained with a balanced technique of volatile anesthetics (isoflurane), muscle relaxation (cisatracurium, vecuronium), and judicious use of narcotics (fentanyl) and benzodiazepines (midazolam).⁶⁵

Monitoring of the coagulation capacity of the recipient is complicated because clotting is usually markedly deranged, and it is necessary to rapidly correct problems. Depletion of coagulation factors and thrombocytopenia are common. Primary fibrinolysis may be evident early in the procedure but does not require treatment in the absence of significant bleeding, which may become problematic during the anhepatic phase. Standard measures of coagulation—prothrombin time (PT), activated partial thromboplastin time (APTT), and platelet count—are very sensitive. However, attempts to correct these values result in excessive transfusion of blood products. There is often significant delay between the time blood is sampled and the results from clotting assays are reported. Finally, standard measures of coagulation provide little timely information about qualitative platelet function and fibrinolysis. Kang and colleagues introduced the thromboelastograph for routine use during OLT.⁶⁶ This test provides the anesthesiologist with a rapid assessment of coagulation status, the presence or absence of fibrinolysis, and the effects of intervention with protamine or ε-aminocaproic acid, an inhibitor of fibrinolysis.^66–68

The surgical procedure involves meticulous dissection, which is often hampered by severe portal hypertension and substantial bleeding from venous collaterals. Insufficient control results in significant blood loss. Identification of the hilar structures may be complicated by adhesions from prior biliary tract surgery. Patency of recipient vessels and adequacy of blood flow must be assessed before placing the graft into the surgical field. An arterial graft for the hepatic artery may be chosen when the recipient anatomy is anomalous or the caliber of the vessels is too small, or when atherosclerosis narrows the celiac trunk. Other indications for an arterial graft include a marked size discrepancy between the recipient and donor vessels and inadequate length of the donor artery. Portal venous thrombosis may be managed with a “jump” graft from the superior mesenteric vein if the portal vein cannot be thrombectomized.⁶⁹ The donor and recipient caval veins are usually anastomosed end-to-end caudad and cephalad to the liver when a cava-sparing technique is not chosen.

Preservation of blood flow in the inferior vena cava (caval preservation) with or without portal drainage is an alternative technique, also known as a piggyback^70–72 and is preferred when there is marked hemodynamic instability. Venovenous bypass was used routinely in the past because it afforded greater hemodynamic stability and reduced mesenteric congestion (Figure 197-2).⁷³ However, the piggyback approach requires one less anastomosis and no dissection of the groin or axilla, decreasing the time for surgery by 1 hour. The biliary anastomosis is fashioned after the vascular anastomoses are completed and the graft reperfused. Two options are used: choledochocholedochostomy or mid-jejunal Roux-en-Y limb with choledochojejunostomy. The former procedure requires less dissection and is restorative. Unfortunately, the stenosis rate is quite high. Diseases which involve the extrahepatic bile ducts, such as sclerosing cholangitis, require resection of the bile duct and creation of a choledochojejunostomy. Stenting of the biliary anastomosis—once routine with a T tube—is now controversial. One innovative approach is cannulation of the donor cystic duct after donor cholecystectomy with a 5F catheter which stents the anastomosis, drains some bile for daily inspection and provides a noninvasive route for cholangiography. A hemorrhoidal band serves to seal the cystic duct once the drain is removed.

Figure 197-2 Venovenous bypass. I.V.C, inferior vena cava; ext. iliac v., external iliac vein.

(From Griffith BP, Shaw BW Jr, Hardesty RL, Iwatsuki S, Bahnson HT, Starzl TE. Veno-venous bypass without systemic anticoagulation for transplantation of the human liver. Surg Gynecol Obstet 1985;160:270-2, with permission.)

Reperfusion is accompanied by cardiovascular collapse in a small (and decreasing) number of patients (∼2%-5%).⁷⁴ Although the exact mechanism is undefined, recirculation results in a cardiac bolus of cold acid and potassium-rich fluid, resulting in acidemia, hyperkalemia, and hypocalcemia. The consequence is abrupt onset of a severe, albeit brief, cardiomyopathy coincident with the loss of vasomotor tone and, occasionally, increased pulmonary arterial pressure. Volume resuscitation, sodium bicarbonate, or THAM for correction of metabolic acidosis, calcium chloride, and inotropic support (epinephrine) are usually sufficient to restore hemodynamic stability. Fortunately, this event is usually short lived. However, significant insults to the graft, heart, kidneys, and brain may occur and require postoperative attention.

Postoperative Management

As might be surmised from the preceding discussion, postoperative management of the OLT recipient is largely governed by the patient’s preoperative condition, the adequacy of the donor organ, and the operative success of the surgical and anesthetic teams. Indeed, the function of the graft is the dominant factor in the recovery of the patient.

Hemodynamic Changes

The characteristic hemodynamic changes of ESLD resolve slowly after OLTX. The exact timing is unresolved, and the controversy likely reflects the preoperative state of some of the patients. Thus, problems resolve more slowly in patients with profoundly deranged liver function and MODS than in recipients who are less ill at the time of transplantation. A vasodilated hyperdynamic state is typical of liver failure^103–107 and rarely normalizes in the immediate postoperative period. Patients who are unable to mount a hyperdynamic response fare worse. Some recipients have preexisting cardiac dysfunction due to ischemic damage or restrictive cardiomyopathy secondary to amyloidosis or hemochromatosis; these patients are unable to increase stroke volume and cardiac output in response to vasodilation. Similarly, patients with sepsis have a higher mortality if they fail to (1) increase ventricular end-diastolic volume to preserve stroke volume as ejection fraction falls and (2) increase heart rate to increase cardiac output.¹⁰⁸ Elevated central venous pressures (CVPs) are transmitted to the hepatic vein and through the liver. Hepatic congestion results in impaired clearance of bacteria, endotoxin, and cytokines. Elevated hepatic venous pressures are reflected in elevated portal pressures, which increase bacterial translocation and endotoxemia, further compromising graft function. Resuscitation must be guided by measurement of CVP. The etiology of hypotension should be classified as cardiac—a consequence of inadequate preload or impaired contractility—or loss of arterial tone.

Management of hypotension requires immediate restoration of adequate circulating volume, usually to a CVP of less than 12 mm Hg. Inotropic support, using dobutamine or epinephrine, should be added if cardiac output remains low despite volume loading. More typically, patients with liver failure are hyperdynamic and vasodilated. In the distributive shock of liver failure, as in septic shock, norepinephrine restores regional blood flow more effectively than dopamine. Low-dose vasopressin (0.04 unit/min) effectively restores perfusion pressure in patients with liver failure. However, vasopressin reduces portal flow and hence hepatic perfusion; these effects obviously might be undesirable in transplant recipients with compromised portal flow. Right ventricular function may be gauged using echocardiography or estimating ejection fraction using a pulmonary artery catheter equipped with a rapid-response thermistor (REF catheter [Edwards Lifesciences]). Marked arterial vasodilation, however, also should prompt an evaluation to exclude a focus of inflammation, infection, pancreatitis, or graft rejection.

Cardiac tamponade should be considered in the differential diagnosis of low cardiac output associated with high filling pressures. There are surgical and medical factors that increase the potential for tamponade. Surgical considerations include the superior aspect of the “Mercedes” incision, which can violate the pericardial parietal reflection, and unintentional inclusion of the right atrium in the superior anastomosis to the inferior vena cava. Medical considerations include impaired coagulation, thrombocytopenia, and renal failure. When tamponade develops in the setting of a hyperdynamic and vasodilated state, cardiac output, calculated systemic vascular resistance, and arterial-venous oxygen content difference all may be deceptively normal.

Although hypotension is a more common problem, arterial hypertension may occur in the postoperative period. It commonly reflects inadequate analgesia or sedation,¹⁶ impaired gas exchange, or hypoglycemia. However, hypertension may persist once these factors are addressed, and attention should then focus on the toxic side effects of cyclosporine^109,110 and tacrolimus. Both drugs are vasoconstrictors and may promote hypertension by activating the renin-angiotensin pathway. This complication occurs more commonly with cyclosporine (30% of cases) than with tacrolimus (10% of cases), and cyclosporine-induced hypertension is more resistant to antihypertensive therapy.^111–113 Antihypertensive therapy should be initiated when systolic blood pressure is over 160 mm Hg or diastolic blood pressure is over 95 mm Hg. We favor combined α- and β-adrenergic receptor blockade with labetalol. Long-term management rests on a combination of β- and α-adrenergic blockade and calcium channel blockade. ACE inhibition may be complicated by hyperkalemia. Hypertension resistant to the first-line agents is usually managed in the ICU with potent vasodilators such as nicardipine and sodium nitroprusside, perhaps in combination with an α-adrenergic blocking agent.

Pulmonary Considerations

Pulmonary complications of ESLD are common.¹¹³ Atelectasis, pleural effusion, reduced functional residual capacity, and limited vital capacity due to ascites and chest wall edema are often present preoperatively. The operative procedure in the upper abdomen, placement of a “normal-sized” graft in the site of a shrunken cirrhotic liver, and postoperative ileus can further decrease vital capacity. Inadequate pain control results in splinting and atelectasis and increases the risk of pneumonia. However, long-term pulmonary sequelae are rare, and most patients have improved pulmonary function tests when studied more than 1 year after OLTX.

Pulmonary infiltrates in patients with liver disease warrant immediate evaluation. Pulmonary infection should be considered, but many pulmonary infiltrates have a noninfectious cause. Pulmonary edema may result from left atrial hypertension (volume overload) or from ALI/ARDS. The latter usually heralds infection, commonly intraabdominal/surgical site with secondary peritonitis. Pancreatitis or liver allograft failure, whether caused by rejection, primary nonfunction, or vascular catastrophe (e.g., hepatic artery thrombosis), may also lead to development of ARDS. When liver failure per se is the cause, ARDS usually resolves after successful transplantation.¹¹⁴ ARDS also may develop during treatment of rejection with thymoglobulin or OKT3.¹¹⁵

Bronchoscopic techniques are used routinely to aid the clinical assessment of pulmonary infiltrates and establish the diagnosis of pneumonia.¹¹⁶ Despite the severe coagulopathy that often is present, bronchoalveolar lavage (BAL) may be performed without significant risk of hemorrhage. Quantitative cultures are obtained, and the presence of bacteria at more than 100,000 colony-forming units (CFU)/mL is considered diagnostic of pneumonia. BAL is sensitive but lacks specificity. A protected brush specimen is less sensitive but more specific. However, it may result in significant endobronchial hemorrhage in coagulopathic patients. With little overall impact on management, we favor BAL. Bronchoscopic techniques confirm the clinical suspicion of pneumonia in only a third of cases.¹¹⁷

Matuschak and associates have described liver-lung interactions.^118,119 ALI is common in advanced liver failure.¹²⁰ Patients with liver failure and ARDS are at high risk for mortality and are usually eliminated as candidates for liver transplantation. However, in highly selected patients with liver failure and ARDS, lung injury resolves quickly after successful OLTX.¹²¹

Two additional pulmonary complications—hepatopulmonary syndrome and portopulmonary hypertension—are unique to patients with liver disease. Cyanosis sometimes occurs in patients with cirrhosis.¹²² Several explanations have been tendered. Anatomic right-to-left shunts have been described within the pulmonary circulation^123,124 and between the portal venous system and the pulmonary veins via esophageal veins.¹²⁵ Increased closing volume resulting in air trapping has been observed. A leftward shift of the oxyhemoglobin saturation curve also has been reported.¹²⁶ Most important, many patients have a diffusion defect manifest as a decreased diffusing capacity (DLCO) on pulmonary function tests. Furthermore, hypoxic pulmonary vasoconstriction is impaired. These findings correlate with anatomic studies showing dilated intrapulmonary capillaries.¹²⁷ Additionally, studies using inert gas washout techniques have demonstrated that hepatic dysfunction is associated with significant ventilation/perfusion mismatching rather than pure shunt. Patients with hepatopulmonary syndrome have dilated pulmonary capillaries which lead to diffusion impairment. Furthermore, increased dispersion in the ventilation/perfusion relationship results in mismatching such that many poorly ventilated units are excessively perfused.¹²⁸ Ventilation/perfusion mismatching does not constitute a true right-to-left shunt, which explains the observation that hyperoxia results from prolonged exposure to high FIO₂. The most useful preoperative test is contrast echocardiography using tiny air bubbles as the contrast agent (“bubble study”). Normally, no contrast agent appears on the left side of the heart after venous injection of the bubbles. The appearance of contrast agent immediately after injection suggests an intracardiac shunt (i.e., patent foramen ovale); contrast agent that appears later (i.e., third to sixth cardiac cycle) suggests intrapulmonary shunting.¹²⁹ Hypoxia usually resolves within the first month, but sometimes resolution is delayed for as long as a year after transplantation. Patients who fail to improve should be investigated with pulmonary angiography to identify a single shunt large enough to be embolized.¹³⁰

Pulmonary hypertension occurs more commonly in patients with cirrhosis than in controls and is called portopulmonary hypertension.¹³¹ Other than cirrhosis, no predisposing factor has been identified. The histopathologic abnormalities in the lungs are typical of primary pulmonary hypertension. Secondary causes of pulmonary hypertension, particularly left ventricular failure, left-to-right intracardiac shunting with increased cardiac output, autoimmune disease, and pulmonary embolism, should be eliminated from consideration, and both portal and pulmonary hypertension confirmed for the diagnosis of portopulmonary hypertension to be established. In an advanced state, it may be difficult to distinguish portopulmonary hypertension from primary cardiac failure with secondary venous congestion and hepatic failure. Portal hypertension can be diagnosed on clinical grounds by the presence of varices, splenomegaly, and can be confirmed by hepatic vein catheterization and measurement of free and wedged pressures, the latter being an estimate of presinusoidal portal pressure. Echocardiography allows estimation of pulmonary pressures by measuring the regurgitant flow velocity through the tricuspid valve. However, confirmation with pulmonary artery catheterization is necessary. Severe pulmonary hypertension recognized only at the start of the OLTX warrants cancellation of the procedure. In contrast to patients with primary pulmonary hypertension, patients with portopulmonary hypertension benefit minimally from acute pharmacologic interventions directed at reducing the pulmonary arterial pressures. Therapeutic measures such as organic nitrates, sodium nitroprusside, or calcium channel blockers fail to reduce pulmonary artery pressure and can lead to systemic hypotension. Low systemic arterial pressure, in turn, may result in right ventricular ischemia, further compromising right ventricular function, with decreased left ventricular filling and cardiac output and more profound hypotension. Initial studies suggested that patients with portopulmonary hypertension are unresponsive to inhaled nitric oxide.¹³² Subsequent experience suggests that inhaled nitric oxide ameliorates pulmonary hypertension and improves arterial oxygenation in some patients.^133,134

An alternative approach borrows from the experience gained by clinicians using continuous infusions of prostaglandins such as epoprostenol (Flolan) to lower pulmonary artery pressure in patients with primary pulmonary hypertension. Prolonged infusion of the drug over weeks or months allows gradual upward titration of the dose,¹³⁵ a tactic that ameliorates pulmonary hypertension without causing systemic hypotension. Cardiac remodeling ensues, leading to improved cardiac output, reduced tricuspid regurgitation, and normalization of CVP. The goal of treatment with epoprostenol is a systolic pulmonary artery pressure (PAP) of less than 60 mm Hg (mean < 40 mm Hg), low CVP, elevated cardiac output, and normal response to fluid challenge (i.e., slight increase in PAP, CVP, and right ventricular end-diastolic volume and a large increase in cardiac output). The change in PAP, CVP, and cardiac output during exercise may provide additional insight and guide perioperative risk assessment and management. However, pulmonary exercise testing does not predict the pulmonary vascular and right ventricular response as systemic hemodynamics normalize after successful transplantation. Pulmonary hypertension resolves in some patients after successful OLTX.^136,137 Others appear to have two concomitant independent processes: pulmonary hypertension (primary) and portal hypertension. Consequently, such patients are at risk for increased PAP and right ventricular failure despite successful OLT. Careful monitoring with PA catheterization and echocardiography is essential. Patients with portopulmonary hypertension treated with epoprostenol require continued infusion and titration during the immediate postoperative period but usually can be weaned over the subsequent year. Although patients with mild pulmonary hypertension (Table 197-5 lists definitions) can tolerate OLTX without significant complications, the picture is bleak for those with moderate to severe pulmonary hypertension (mean PAP > 45 mm Hg). Most transplant recipients with severe pulmonary hypertension die of right-sided heart failure during reperfusion or during the early recovery phase. They tolerate large fluid shifts poorly. Right ventricular overload and failure develop abruptly, compromising the viability of the graft as a consequence of hepatic and mesenteric congestion. Low cardiac output and hypotension results in graft ischemia and death. Poorly controlled pulmonary hypertension or residual right ventricular dysfunction presents an absolute contraindication to liver transplantation.

TABLE 197-5 Pulmonary Hypertension and Liver Disease

PA, pulmonary artery.

Pulmonary hypertension that develops de novo during or acutely after liver transplantation may result from embolic phenomena at the time of transplantation that may be evident on intraoperative transesophageal echocardiography. Patients should be managed with attention to sustaining right ventricular coronary perfusion by maintenance of adequate mean arterial pressure and avoidance of central venous hypertension. Pulmonary hypertension can develop late after liver transplantation. This problem is not always directly related to portal hypertension, because liver function and the transhepatic venous pressure gradient (pressure difference between wedged and free hepatic venous pressures) may be normal.¹³⁸

Clinically valuable alternatives to prostaglandins include endothelin receptor antagonists (ERA) and phosphodiesterase-5-inhibitors. However, experience is limited with these agents in portopulmonary hypertension. Bosentan is a nonselective ERA which improved exercise tolerance. However, it may cause cholestasis which usually were versus upon discontinuation. Ambrisentan is a selective ERA associated with less cholestasis. Significant reduction in pulmonary artery pressures and right ventricular remodeling in the setting of portopulmonary hypertension remains to be demonstrated. Phosphodiesterase-5 inhibitors such as sildenafil lower PAP and may be used alone or in conjunction with prostaglandins and endothelin inhibitors.

Mechanical ventilatory support is often required preoperatively for patients with ESLD. Intubation to minimize aspiration is required when the patient cannot protect the airway because of encephalopathy or massive upper GI hemorrhage. Respiratory failure can be precipitated by volume overload and pulmonary edema, infection, or profound muscle weakness. The increased risk of ALI/ARDS warrants mechanical ventilation with a low tidal volume strategy determined by a height-based calculation of ideal body weight.¹³⁹ We favor a pressure-limited approach for most patients, using CPAP/PS or pressure control-IMV. Sedation should be minimized and early mobilization out of bed with standing and ambulation attempted, even with an endotracheal tube, significant PEEP, and vasopressor support, with careful monitoring. Early extubation is indicated as soon as the patient can clear secretions, protect the airway, and ventilate without fatiguing. Hypoxemia can be managed with supplemental oxygen and positive airway pressure provided with CPAP. Previously, the median duration of intubation after transplantation was 2 days. Recent changes in anesthetic techniques allow many patients to be extubated in the PACU. Now the median duration of intubation for patients who require ICU admission is less than 24 hours. Early extubation postoperatively (<6 hours) is the goal, and immediate postoperative extubation is possible in those having an uncomplicated intraoperative course and no life-threatening premorbid extrahepatic organ dysfunction.^140,141

Renal Considerations

Renal dysfunction in patients with liver disease is frequently unrecognized. Liver dysfunction and malnutrition make elevations in blood urea nitrogen and serum creatinine concentration unimpressive despite a significant decrease in glomerular filtration rate (GFR). Preoperative renal failure (creatinine > 2.0 or the need for hemodialysis) presages post-operative renal failure and decreased survival.^142,143 Kidney biopsy may help guide a decision for combined kidney and liver transplantation.¹⁴⁴ In the posttransplant period, several factors conspire to impair renal function. These factors include preoperative renal failure (hepatorenal syndrome), episodic arterial hypotension resulting in tubular damage, medications (e.g., cyclosporine, tacrolimus, and vasopressors) that cause renal arterial vasoconstriction, and amphotericin, which causes tubular damage.¹⁴⁵ Furthermore, liver allograft dysfunction leads to portal and mesenteric hypertension which leads to functional renal impairment—the hepatorenal syndrome. Renal replacement therapy is required for approximately 10% of patients. Continuous renal replacement offers greater hemodynamic stability and may not precipitate additional organ injury. Adequate renal perfusion pressure requires at least “normal” mean arterial pressure. However, there seems to be little benefit to the kidney from dopamine, fenoldopam, calcium channel blockade, or prostaglandin infusion.

Gastrointestinal Considerations

Protein and calorie malnutrition is common in liver failure; it is a catabolic process. Weight and appearance are often misleading, and cachexia is evident once anasarca resolves. Muscle wasting may be most apparent in the temporalis and thenar eminence. Malnutrition compromises the outcomes from liver transplant, resulting in higher perioperative complications and mortality. Recognition and preoperative treatment of malnutrition may improve liver transplant outcomes. Gastroparesis is common in liver failure, increasing the risk of aspiration pneumonitis and pneumonia. We use nasojejunal feedings in malnourished patients who demonstrate inadequate intake of calories and protein. Enteral nutrition may be initiated or restarted within 6 hours after liver transplant for patients with a choledochocholedochostomy. Further delay up to 72 hours may be required in patients with a choledochojejunostomy and jejunojejunostomy (Figure 197-3) to resume full-dose enteral nutrition, although slower rates are often tolerated. On rare occasions when parenteral nutrition is required, we use crystalline amino acids and supply one-third of the nonprotein calories as fat. This approach minimizes glucose intolerance, which is common in the early post-OLTX period.

Figure 197-3 Choledochojejunostomy and choledochocholedochostomy.

(From Starzl TE, Demetrius AJ, Van Thiel D. Liver transplantation (1). N Engl J Med 1989;321:1014-92, with permission.)

Upper GI bleeding in the OLTX recipient is uncommon, but prompt investigation is mandatory when it occurs. Gastritis and stress ulceration are common causes. Recurrence of esophageal and gastric varices often reflects diminished portal vein blood flow or complete thrombosis. Bleeding distal to the ligament of Treitz may be from the site of the jejunojejunostomy. Visualization may require a pediatric colonoscope. Revision of the anastomosis may be unnecessary in most patients by correction of coagulation.

Bleeding from the GI tract weeks or months after surgery should prompt an evaluation for infectious causes such as cytomegalovirus (CMV) infection or Clostridium difficile enterocolitis. Bleeding may be a manifestation of neoplastic GI involvement with lymphoma. Mesenteric and splenic artery aneurysms are associated with portal hypertension and may rupture postoperatively. These lesions are usually recognized at postmortem examination. However, some patients develop an arterioenteric fistula and present with massive GI hemorrhage. Angiography can confirm the diagnosis in more stable patients but should not delay exploration, because rapid surgical repair is mandatory.

Pancreatitis is a feared but less common complication of OLTX. Although nearly 20% of patients demonstrate elevated serum amylase or lipase levels, 5% or less have clinically significant pancreatitis.¹⁴⁶ Conservative measures are effective in mild cases. Management of severe pancreatitis is as controversial in this setting as it is in patients without OLTX. The roles of somatostatin and operative débridement with continuous lavage remain to be defined.

Neurologic Considerations

Patients with minimal pretransplant hepatic encephalopathy who have an uncomplicated operation and receive a well-functioning graft recover rapidly from anesthesia. Changes in mental status require a thorough evaluation. Most commonly, the side effects of immunosuppressive agents such as cyclosporine and tacrolimus may be incriminated and demonstrated by resolution within 7 to 10 days of lower levels. Occasionally, discontinuation of calcineurin inhibition is necessary. Focal deficits should prompt concern about the possibility of embolic or hemorrhagic complications. Intracranial infection is rare in the early postoperative period but should be considered in patients with headache and confusion.

Patients with early graft dysfunction also often have changes in mentation. Graft swelling may result in portal congestion and portosystemic shunting. Administration of flumazenil may produce a more awake but still encephalopathic patient. The exact mechanism for encephalopathy due to graft dysfunction remains to be elucidated. Side effects of medications assume a much greater role in such patients. Clearance of commonly used immunosuppressive agents, analgesics, sedatives, and hypnotics is impaired. The amnestic effects of some agents may compound the problem. We use boluses of fentanyl for analgesia, as it is short acting and has no active metabolites. Benzodiazepines exacerbate delirium, so if sedation is needed, we prefer infusion of propofol,¹⁴⁷ with frequent titration and daily discontinuation. Delirium, which is more commonly akinetic than agitated and thus often unrecognized, responds better to low doses of haloperidol or atypical antipsychotics such as olanzapine and quetiapine. Sleep in the ICU is abnormal and made worse by commonly used medications.¹⁴⁸ Unlike benzodiazepines and other sedative hypnotics, dexmedetomidine can be titrated to effect without disrupting normal sleep patterns.^149,150

The seizure threshold is lowered by several medications used in liver transplant recipients, including cyclosporine, tacrolimus, thymoglobulin, and antipsychotics.^151,152 Hypoglycemia, electrolyte abnormalities including hyponatremia and hypomagnesaemia, and metabolic acidosis further lower the seizure threshold.

Nonconvulsive or akinetic seizures, although rare, are more common in this ICU subpopulation and should be considered in the differential diagnosis of the comatose patient. Continuous EEG allows seizure detection as well as assessment of the effectiveness of treatment. Refractory status epilepticus may require induction of coma. Propofol causes less hypotension than pentobarbital and can be titrated to burst suppression of 5 to 10 seconds.

Additional aspects of neurointensive care need consideration in patients with ALF. These patients have encephalopathy that is mediated in part by the γ-aminobutyric acid (GABA) pathway, as is the case for patients with the portosystemic encephalopathy of chronic liver disease.¹⁵³ But patients with ALF develop intracranial hypertension and cerebral edema.¹⁵⁴ Patients in grade III and grade IV coma should have ICP monitored. Improved fidelity but increased complications such as bleeding and infection vary with the invasiveness of the monitoring technique.¹⁵⁵ A parenchymal monitor such as Codman or Camino offers a much better signal-to-noise ratio with only slight increase in risk. Ventriculostomy is the approach utilized at our institution and offers the therapeutic advantage of draining cerebrospinal fluid to avoid transient increases in intracranial pressure, with attendant decrements in cerebral perfusion pressure, minimizing compounding ischemic insults. This purported advantage is somewhat offset by bleeding around the ventriculostomy catheter which has been evident on computed tomography (CT) but clinically asymptomatic. Cerebral blood flow (CBF) can be measured with xenon-133 or with cold xenon as contrast for CT scanning. Cerebral oxygen consumption can be determined after placement of a jugular bulb catheter.¹³⁶ Cerebral metabolic rate (CMRO₂) is related to the product of the CBF and arterial-venous oxygen content difference (AJVdO₂ = CaO₂ − CjvO₂) according to the following formula:

Intracranial hypertension may result from increased CBF (blood volume) or brain swelling (cerebral edema). Elevated CBF with normal oxygen consumption is associated with narrow AJVdO₂ and is termed luxuriant perfusion. Subsequently, cerebral edema with intracranial hypertension develops and is associated with decreased CBF and large AJVdO₂.¹⁵⁶ Management of intracranial hypertension is guided by the observed pathophysiology. Elevated ICP with increased CBF responds to hyperventilation, reduction in intravascular volume, and hypothermia. Intracranial hypertension with low CBF must be treated by increasing cerebral perfusion pressure by increasing mean arterial pressure. Osmotic agents including mannitol and hypertonic saline are also appropriate at this stage, with diuretics or CRRT to minimize elevation in CVP. Hypothermia restores cerebral autoregulation^157–159 induced by ALF. It effectively lowers ICP¹⁶⁰ and can be titrated to effect. Induction of coma with propofol titrated to burst suppression with continuous EEG monitoring may lower ICP further. However, accumulation of vasodilatory metabolites will compromise cerebral perfusion pressure. Patients are considered viable candidates for OLTX as long as EEG activity is preserved and adequate cerebral perfusion pressure and CBF can be maintained. Intraoperative monitoring includes these measures, combined with transcranial Doppler measurements of flow velocity contour in the middle cerebral artery,¹⁶¹ which facilitate moment-to-moment titration of anesthetics and vasopressors. Although the initial period of graft reperfusion is the most hazardous, cerebral hyperemia and intracranial hypertension may persist for several days postoperatively. These abnormalities usually resolve with good graft function.

Liver transplant recipients are at risk for neuromuscular dysfunction. In a prospective study of 100 liver transplant recipients, clinically relevant weakness, defined as weakness requiring prolonged mechanical ventilatory support, developed in 7% of patients. Electromyography demonstrated that weakness was due to a myopathic rather than neuropathic process, and diffuse myocyte necrosis was evident on muscle biopsy specimens taken from five patients.¹⁶² Predisposing factors included patient acuity postoperatively as judged by the APACHE II score, poor liver allograft function at 1 week, a requirement for renal replacement therapy, and higher doses of corticosteroids. Patients requiring early retransplantation seemed to be at particular risk.

Infectious Complications

Rejection of the allograft is treated aggressively when it develops. These measures are often complicated by the parallel development of infections. Heavily immunosuppressed patients die not of rejection but of infection. The paradigm is that immunosuppression sufficient to eliminate rejection results in a defenseless host susceptible to many infections. Solid organs vary in their propensity to stimulate rejection. The liver is relatively less immunogenic; accordingly, immunosuppression can be less intensive but still be effective. In the early postoperative period, bacterial and fungal infections are common. The most frequently involved areas are the operative site and the lungs. Perioperative antimicrobial prophylaxis targets gram-negative rods and enterococci and consists of a second- or third-generation cephalosporin or ampicillin-sulbactam and is continued for 48 hours. Prophylactic regimens vary among centers. Unfortunately, antimicrobial resistance is common, and isolates in patients who die of an infectious process are occasionally resistant to all known antimicrobial agents.¹⁶³

Fungal colonization is also common. Patients requiring a prolonged, difficult surgical procedure and multiple transfusions of blood products are at higher risk for fungal infection, as are patients undergoing retransplantation.^164,165 Prophylactic antifungal therapy reduces the incidence of both superficial and deep fungal infections. Options include fluconazole,¹⁶⁶ amphotericin (10-20 mg daily for the first 2 weeks after surgery), or full doses of amphotericin B liposomal complex (ABLC) in the subgroup at highest risk of filamentous fungal infection—patients with renal and liver failure prior to OLT and those with ALF.¹⁶⁷ Patients with significant growth of Candida spp. on quantitative culture of BAL often require a full course of amphotericin.^168,169 The outcome has improved for liver transplant recipients who develop Aspergillus infection. This previously fatal infection¹⁷⁰ seems more responsive to voriconazole¹⁷¹ or liposomal forms of amphotericin such as AmBisome.

Late after transplantation, infections reflect the specific effects of immunosuppressive agents on T-cell function. Although bacterial and fungal infections occur, viral infections and infections caused by opportunistic pathogens become more important. Pneumonia due to Pneumocystis jiroveci (formerly carinii) was common before the advent of routine prophylaxis with trimethoprim-sulfamethoxazole. Its occurrence now is limited to those for whom prophylactic measures have been stopped.

CMV infections are common in the transplant population.^172,173 However, the clinical severity of infection is quite variable. Some cases are asymptomatic. Others present as a viral syndrome, involve only one organ such as the lungs, GI tract, or liver, or involve multiple organs. The patients at highest risk for CMV infection are those who were seronegative before OLTX and received an organ from a seropositive donor. It is debatable whether patients who were seropositive before OLTX experience reactivation of latent virus or are infected by another CMV strain. In addition to the morbidity and mortality attributed directly to CMV, patients with CMV disease also have a higher frequency of bacterial and fungal infections. Increased susceptibility to bacterial and fungal infections may be a function of the CMV infection per se or reflect more aggressive immunosuppression—an independent risk factor for CMV infection. Seroconversion may not occur until T-cell immunosuppression is withdrawn.¹⁷⁴

Prophylaxis with ganciclovir¹⁷⁵ or CMV immunoglobulin^176,177 is effective but with significant penalty in terms of side effects such as neutropenia and costs borne by all for benefit of a few. An alternate strategy is to monitor patients closely for evidence of CMV disease. CMV viremia can be detected by PCR or by assaying for the CMV the pp65 antigen.¹⁷⁸ Thresholds for treatment can be varying in relation to the risk of CMV disease in a particular subpopulation. Ganciclovir and valganciclovir are the mainstays of treatment, with foscarnet reserved for patients with intractable severe neutropenia and when resistance is suspected.

Endocrine Considerations

Hyperglycemia is common in the early postoperative period and reflects the combination of surgical stress, corticosteroids, and calcineurin inhibition. A survival benefit of intensive insulin therapy has been demonstrated^179,180 but is of unclear benefit in unselected ICU patients.¹⁸¹ We suspect the high incidence of infection and neuromuscular disease in liver transplant recipients warrants intensive insulin therapy with a rationale similar to burn-injured patients.^182–185 We have modified the approach described by Davidson¹⁸⁶ to minimize hypoglycemia and target glucose of 90 to 120 mg/dL.

Adrenal insufficiency is common in critically ill patients with liver disease.¹⁸⁷ Both primary and secondary adrenal insufficiency may be unmasked by stressors such as infection, graft dysfunction, pancreatitis, or bleeding. Measurement of baseline serum ACTH and cortisol and subsequent response of serum cortisol to cosyntropin allow recognition of adrenal insufficiency and classification. The indication for continued treatment with “stress-doses” of hydrocortisone can then be determined.

Thyroid dysfunction, particularly hypothyroidism, is common in patients with primary biliary cirrhosis and in autoimmune hepatitis and may be heralded by changes in mentation which may mistakenly be attributed to the precipitating stressor. More commonly, normal thyroid function by clinical exam is associated with low total thyroxine (T₄) but normal free T₄ and thyroid-stimulating hormone (previously described as “euthyroid-sick”). However, newly diagnosed and treated hypothyroidism should also be managed with sufficient corticosteroids to preclude an Addisonian crisis.

Conclusion

Patients with terminal liver disease can undergo successful transplantation. Critically ill patients with ESLD have dramatic improvement in their quality of life. Intensive care of such patients is demanding but highly rewarding. Recipient acuity, donor risk index, and institutional resources must be carefully assessed for each high-risk transplant to be successful. The transplant intensivist should participate in this risk/benefit analysis with the transplant hepatologist, surgeon, and anesthesiologist. In addition to ICU care, the intensivist provides support and guidance for “fast-tracked” patients to be managed safely outside the postanesthesia care unit (PACU) and ICU. Developments in the future will focus on optimal candidate selection and more precise immunosuppression.

Key Points