Chapter 33

The Transplant Patient

Andrew S. Barbas and Anand Ghanekar

Chapter Overview

Perioperative critical care of the transplant recipient can be challenging, with multiple considerations across several organ systems that require management simultaneously. The principles of managing organ transplant recipients specifically include optimizing hemodynamic and metabolic parameters to ensure satisfactory graft perfusion, monitoring graft function and managing graft dysfunction, and preventing or managing potential complications of the underlying disease, transplant surgery and immunosuppression. This chapter will focus primarily on critical care of the liver transplant recipient, as these patients are the most commonly encountered transplant recipients in a typical surgical intensive care unit (ICU) and serve to illustrate many important considerations typical of recipients of other types of solid organ transplants.

As a field, liver transplantation has progressed dramatically since its origin in the 1960s. Advances in surgical technique, anesthetic management, perioperative critical care, and immunosuppression have led to consistently safe performance of liver transplantation in the modern era.

Currently over 20,000 liver transplants are performed annually worldwide for a variety of indications. The perioperative mortality in experienced centers is less than 5%, with expected 1 year and 5 year survival of 90% and 75%, respectively. The primary indications for liver transplantation are decompensated liver disease with an expected survival of less than one year, or hepatocellular carcinoma limited to the liver. Contraindications for liver transplantation include severe cardiopulmonary disease, active sepsis, and extrahepatic malignancy.

Several neurologic issues may affect liver transplant patients. Perhaps the most important is hepatic encephalopathy. Prior to transplantation, hepatic encephalopathy is common, with nearly 50% of cirrhotic patients displaying some degree of impairment. The degree of encephalopathy is graded on a scale from 1–4 (Table 1). The biochemical mechanisms responsible for the development of hepatic encephalopathy are not fully elucidated, but it is hypothesized that the failing liver is unable to appropriately clear ammonia and other metabolic byproducts that alter neurotransmitter activity in the brain. Hepatic encephalopathy is often triggered by specific events, such as the development of an infection, gastrointestinal (GI) bleed, or placement of transjugular intrahepatic portosystemic shunt (TIPS).³ Closely related to hepatic encephalopathy is the development of cerebral edema, almost exclusively seen in the setting of acute liver failure with high grade encephalopathy (grade 3–4). Ammonia and other chemical mediators are associated with neuronal and astrocyte swelling, contributing to the development of cerebral edema.1 Additionally, the failure of cerebral blood flow autoregulation mechanisms may contribute to the pathogenesis. In its most severe form, cerebral edema ultimately progresses to coma, brainstem herniation, and death.

Table 1. Severity of hepatic encephalopathy.

The treatment of mild hepatic encephalopathy includes reduction of dietary protein intake in order to limit the generation of ammonia and metabolic byproducts, administration of lactulose to acidify GI tract contents and reduce GI absorption of ammonia, and treatment with rifaximin targeting gut bacteria that produce ammonia. In severe (grade 3 or 4 hepatic encephalopathy) with associated cerebral edema, treatment strategies aimed at managing elevated intracranial pressure (ICP) are also necessary. The central principle in managing patients with elevated ICP is maintenance of adequate cerebral perfusion pressure (CPP). Cerebral perfusion pressure is calculated as the difference between mean arterial pressure (MAP) and ICP (CPP = MAP − ICP). Goals of treatment are to maintain CPP at 60−70 mmHg. Several interventions can be used to optimize CPP. Generally, patients in this state require intubation and mechanical ventilation to secure their airway and ensure appropriate gas exchange. Maneuvers to reduce elevated ICP include elevation of the head of bed to 30°, hyperventilation to achieve a PCO₂ of 35 mmHg (temporary measure), and administration of mannitol and hypertonic saline to draw interstitial fluid from the brain. In severe cases, invasive ICP monitoring may be necessary, which also may allow drainage of cerebrospinal fluid to lower ICP.6

Postoperatively, normal graft function is expected to facilitate rapid recovery of pre-existing hepatic encephalopathy. Close attention must be paid to the recipient’s mental status, as failure of normalization can be indicative of impaired graft function. Additionally, patients recovering in the ICU following liver transplantation are also vulnerable to the common postoperative neurologic issues that affect the entire ICU population such as delirium and critical illness polyneuropathy. Treatments for these conditions are similar to those employed for non-transplant patients and discussed elsewhere in this text. A unique consideration in post-transplant patients is the potential for Central Nervous System (CNS) side effects of calcineurin inhibitors. Although, tacrolimus is more commonly used in the current era, both cyclosporine and tacrolimus have several potential associated neurotoxicities. Symptoms can include the development of tremors, headaches, seizures, focal neurologic deficits, and in rare cases the development of posterior reversible encephalopathy syndrome (PRES).4 PRES is characterized by a constellation of symptoms that include severe headache, altered level of consciousness, visual disturbances, and seizures. Neuro-imaging typically demonstrates findings of symmetrical white matter edema in the posterior cerebral hemispheres, particularly the parietal and occipital lobes. Neurologic side effects from calcineurin inhibitors can generally be ameliorated by dose reduction or the substitution of alternative agents.

Cardiovascular

Liver transplantation imparts a significant physiological stress on the cardiovascular system. In general, patients are only activated on the transplant waitlist after undergoing careful preoperative assessment of their cardiac function, including cardiac catheterization if necessary. Severe underlying cardiovascular pathologies such as extensive coronary artery disease, valvular abnormalities, and congestive heart failure are absolute contraindications to proceeding with liver transplantation. Despite careful preoperative evaluation, occult cardiac abnormalities may be unmasked by the significant physiologic stress associated with liver transplantation. From an abdominal surgery perspective, there are few procedures as physiologically taxing as liver transplantation. Operations are commonly long in duration with significant blood loss. Additionally, in the classic surgical technique, the inferior vena cava (IVC) is fully clamped in the anhepatic phase, and cardiac preload is completely dependent on venous return from the upper body. Many patients require significant vasopressor support and fluid administration to maintain adequate blood pressure during this period. Another particularly challenging phase of the operation from a physiologic perspective occurs during reperfusion of the transplanted liver. Following completion of the IVC and portal vein anastomoses, these vessels are unclamped and the transplanted liver is reperfused. This imparts a sudden increase in venous return to the right heart, and the initial blood return is significantly cooler than body temperature and rich in potassium and lactate from the preservation solution. The sudden bolus of cold, potassium rich blood can lead to acute right heart dysfunction and potentially lethal arrythmias. Extreme vigilance on the part of the anesthesia and surgical teams is critical during this phase of the operation. These significant physiologic demands can also induce cardiac ischemia and subsequent myocardial infarction.

Large volume shifts and third spacing of fluids is typical in the early postoperative period, and aggressive fluid resuscitation is frequently necessary to maintain sufficient circulating volume and graft perfusion. When possible, rapid weaning of vasopressor agents is important to reduce the risk of hepatic artery thrombosis. While significant fluid administration is commonly required early, as recovery progresses, careful attention should be paid to avoid volume overload with elevations of central venous pressure, which may lead to liver congestion and graft dysfunction. Maintenance of electrolyte equilibrium and euvolemia are also essential for avoiding the development of atrial fibrillation. These considerations become even more important considering the increasingly elderly patient population undergoing liver transplantation.

In addition to the physiologic stress of the procedure itself, there are specific pathophysiologic changes from end stage liver disease and cirrhosis that affect the cardiovascular system and have implications for postoperative management. Patients with advanced liver disease and cirrhosis commonly exhibit decreased systemic vascular resistance (SVR) secondary to neurohormonal changes affecting the central, splanchnic, and peripheral vascular beds. Consequently, cirrhotic patients frequently exhibit a lower baseline mean arterial pressure, which should be taken into account when managing vasoactive medications in this population. The decreased SVR induces hyperdynamic circulatory physiology, and management of this high cardiac output state may require invasive monitoring including pulmonary artery catheterization. Additionally, approximately 50% of cirrhotic patients exhibit a constellation of abnormalities in cardiac function collectively termed cirrhotic cardiomyopathy. This is characterized by systolic dysfunction and abnormal diastolic relaxation, exacerbated during times of physiologic stress. Additional features include prolongation of the QT interval and elevated brain natriuretic peptide (BNP). The mechanisms underlying this phenomenon are related to altered function of ion channels and beta adrenergic receptors as well as alterations in myocyte morphology and function.5,13 In addition, the specific disease process that has led to liver failure may also have systemic manifestations which include cardiovascular pathology. Wilson’s disease, hemochromatosis, amyloidosis, and alcoholic cirrhosis are all characterized by concomitant non-ischemic cardiomyopathy which must be carefully managed in the perioperative period.

Pulmonary

There are several important pulmonary considerations relevant to postoperative care of the liver transplant recipient. Co-existing pulmonary pathology is common in patients with liver disease and ranges in severity from relatively benign to life threatening. Patients with large volume ascites from portal hypertension also commonly have accompanying pleural effusions, also known as hepatic hydrothorax. This is generally caused by the translocation of ascites from the abdomen into the chest through pores in the diaphragm. If pleural effusions reach sufficient size they may impair pulmonary function and require drainage in the perioperative setting.

Patients with advanced cirrhosis are also at risk for the development of specific abnormalities in the pulmonary circulation due to the systemic neurohormonal derangements affecting the vasculature throughout the body. Hepatopulmonary syndrome is characterized by abnormal dilatation of pulmonary capillary beds, leading to intrapulmonary shunting and subsequent hypoxemia, and can be found in up to 30% of patients undergoing liver transplantation. This may also be accompanied by the development of direct arteriovenous communications within in the lung, which further contribute to hypoxemia. Overproduction of pulmonary nitric oxide is thought to be an important contributor to the pathophysiology, although the mechanisms are not fully elucidated. Clinical manifestations of hepatopulmonary syndrome may include dyspnea on exertion or at rest, digital clubbing, and orthodeoxia: The drop in partial pressure of oxygen (PO₂) in arterial blood when changing positions from supine to upright. The primary diagnostic study to help establish the diagnosis is transthoracic echocardiography (ECHO) with micro-bubble examination. In this study, agitated saline with microbubbles is administered through a peripheral vein, and the appearance of these bubbles in the left heart after 3–6 beats is indicative of a right to left shunt through abnormally dilated pulmonary capillaries. The severity of hepatopulmonary syndrome is characterized on a range from mild to very severe, based on the partial pressure of oxygen in arterial blood gas (Table 2). There are no effective medical therapies to reverse this phenomenon preoperatively, and management consists primarily of supportive care and administration of oxygen. Fortunately, liver transplantation frequently leads to resolution over weeks to months.⁹

Portopulmonary hypertension is another important derangement in pulmonary circulation associated with liver disease, although the pathophysiology differs significantly from hepatopulmonary syndrome. Portopulmonary hypertension is characterized by increased pulmonary vascular resistance and elevated pulmonary artery pressure in the setting of portal hypertension. It is formally defined by a mean pulmonary arterial pressure ≥ 25 mmHg, pulmonary vascular resistance > 240 dyn-sec-cm⁻⁵, and pulmonary capillary wedge pressure < 15 mmHg. It is a relatively rare complication, affecting 6–8% of cirrhotic patients, and does not seem to be related to the etiology or severity of the underlying liver disease. Portopulmonary hypertension is categorized as mild, moderate, or severe based on the mean pulmonary artery pressure by right heart catheterization (Table 2). The biologic mechanisms contributing to portopulmonary hypertension have not been fully elucidated but the development is thought to be related to aberrations of circulatory mediators and cytokines including endothelin-1 and IL-6. Clinical manifestation ranges from completely asymptomatic to dyspnea on exertion, and screening echocardiography generally demonstrates an elevated right ventricular systolic pressure. Formal diagnosis requires right heart catheterization to measure mean pulmonary artery pressure and pulmonary vascular resistance. Liver transplantation is considered unsafe in patients with moderate and severe portopulmonary hypertension due to prohibitively high morbidity and mortality rates. The goal of medical management of these patients is to reduce pulmonary artery pressure to a safe range. Many agents have demonstrated efficacy in improving pulmonary artery pressures including inhaled or infusional prostaglandin therapy, phosphodiesterase inhibitors such as sildenafil, and endothelin receptor antagonists. Liver transplantation has been shown to be safe in patients in whom pulmonary hypertension can be medically managed, and in many cases is curative of this process.¹⁰

Table 2. Clinical features and grading of hepatopulmonary syndrome and portopulmonary hypertension.

In liver transplant recipients with either hepatopulmonary syndrome or portopulmonary hypertension, a more difficult postoperative recovery can be expected with potential for prolonged need for mechanical ventilation. However, in typical recipients who are otherwise stable clinically, many intensive care units have adopted a policy of early ventilator weaning and extubation. In many of these units, a protocol based weaning approach executed by respiratory therapists and the bedside nursing staff have been used to achieve effective rapid weaning and extubation following liver transplantation. Overall, these programs have been shown to decrease duration of mechanical ventilation, complication rate, and costs of ICU care.8

Renal

Pre-existing renal dysfunction is common in patients with advanced liver disease, and acute kidney injury is common in the perioperative period following liver transplantation, creating significant challenges in the management of volume status, electrolytes, and acid–base status postoperatively.

A significant percentage of patients have pre-existing renal dysfunction prior to liver transplantation. This can be multifactorial, but one of the primary contributors is the development of hepatorenal syndrome (HRS), which is a functional renal failure specific to patients with end stage liver disease or fulminant hepatic failure, characterized by acute kidney injury without obvious parenchymal pathology (Table 3). The pathophysiology underlying HRS is characterized by vasodilation of the splanchnic circulation, mediated in part by abnormally high levels of nitric oxide. In turn, this sequestration of blood volume in the splanchnic circulation leads to a diminished effective circulating volume, thus initiating several compensatory mechanisms. These include the activation of the renin–angiotensin–aldosterone system (RAAS), sympathetic nervous system, and increased production of anti-diuretic hormone (ADH)/vasopressin. These compensatory mechanisms are similar to those initiated by pre-renal causes of kidney failure, and over time lead to renal vasoconstriction, acute kidney injury, and diminished glomerular filtration rate (GFR). Consistent with this pre-renal physiology, urine sodium is usually low in HRS (< 10 mEq/L), distinguishing it from acute tubular necrosis (ATN). Two variants of HRS are described in the literature, with significantly different clinical implications. HRS type 1 is characterized by a relatively acute deterioration in kidney function with a doubling of serum creatinine to a level > 2.5 mg/dL within a two week time frame. It is usually initiated by a precipitating insult such as an infection, and subsequent multisystem organ failure is common. Prognosis in HRS type 1 is poor, with only a 10% survival at 3 months. HRS type 2 follows a more gradual deterioration in renal function and usually is associated with the development of ascites. Median survival of patients with HRS type 2 is 6 months.

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