Intravascular Fluid Management

Brainstem injury produces a sequence of hemodynamic events, beginning with an increase in parasympathetic tone and evolving to a massive autonomic surge with hypertension (systolic blood pressure > 200 mm Hg) and tachycardia (>140 beats/min) (Audibert et al., 2006). The pathophysiology of neurocardiogenic injury involves an initial neural phase (catecholamine surge and mixed venous oxygen saturation [MVo₂] supply-demand imbalance) within hours, followed by a humoral phase and release of inflammatory cytokines. Depletion of thyroid hormones and cortisol, and decreased coronary perfusion pressure may also impair myocardial function. Coronary vasoconstriction, subendocardial ischemia, focal myocardial necrosis, and endothelial injury are factors that contribute to accelerated cardiac allograft vasculopathy in the recipient (Segel et al., 2002; Szabo et al., 2002; Mehra et al., 2004). Systolic and diastolic dysfunction has been reported in 10% to 28% of pediatric donors and 71% of adult donors. It is reversible in the majority of cases (Banki and Zaroff, 2003). Despite normal or increased perfusion pressure, the resulting vasoconstriction may cause tissue ischemia that disrupts the production of ATP, generates oxygen free radicals, increases cytosolic calcium concentration, and activates various enzymatic cascades such as endonucleases and nitric oxide syntheses (Kunzendorf et al., 2002). A subsequent hypotensive phase caused by loss of autonomic regulation of the peripheral vasculature and unopposed vasodilation may further reduce oxygen supply to the tissues. Hypovolemia is seen with diuresis and fluid restriction during brain resuscitation, inadequate volume replacement after trauma, and diuresis resulting from diabetes insipidus or hyperglycemia.

Brain death is a dynamic inflammatory process. The activation of inflammatory mediators leads to a nonspecific immune response, which may be associated with accelerated acute graft rejection and poor long-term outcomes (Kunzendorf et al., 2002). In addition, a significant factor in organ injury after storage and cold ischemia is caused by reperfusion, initiated by leukocyte adhesion to endothelial cells and the production of oxygen-derived free radicals and peroxides.

Fluid replacement therapy with colloid or crystalloid solutions and cytomegalovirus (CMV)-negative blood products directed at restoring and maintaining the intravascular volume is the first step in resuscitation of the hemodynamically unstable donor. Use of lactated Ringer’s solution, normal saline, Plasmalyte, or 5% albumin, is recommended, starting with a 20-mL/kg intravenous (IV) bolus and followed by hemodynamic reassessment of the donor and two additional boluses as needed. The lowest acceptable systolic blood pressure can be calculated by multiplying the patient’s age in years by 2, and adding 70. Hypotonic and dextrose-containing crystalloid solutions should never be used for fluid resuscitation. Hetastarch (Hespan) or other artificial plasma expanders should be avoided for fluid resuscitation because of their inherent risk for coagulopathy and renal impairment. Volume loading with crystalloid- or colloid-containing solutions usually depends on institutional preference and the sensitivity of the liver and lungs to low osmotic pressure–mediated tissue edema. When only the kidneys are to be procured, the donor can be maximally volume loaded. For lung or heart-lung retrieval, fluid restriction (CVP ≤ 6 mm Hg) is preferred. Infusion of colloids is recommended, with limited use of crystalloid and early initiation of inotropic support to maintain a mean arterial pressure of 60 mm Hg or greater.

If the initial two-dimensional echocardiographic evaluation reveals that the left ventricular ejection fraction is less than 45%, management with invasive monitoring, fluids, inotropes, vasopressors, hormonal, replacement therapy (with hydrocortisone, levothyroxine, or triiodothyronine), and treatment of diabetes insipidus (with desmopressin [DDAVP] or vasopressin infusion) is strongly recommended (Table 28-8).

TABLE 28-8 Maintaining Mean Arterial Pressure in the Pediatric Organ Donor

Corticosteroids

Corticosteroids were the initial mainstay of therapy for organ transplantation, but their use is on the decline. They are particularly effective in both the prevention and treatment of acute rejection episodes. Their predominant mechanisms of action include the inhibition of IL-1 and IL-2 production, suppression of helper and suppressor T cells, suppression of cytotoxic T cells, and reduction in the migration and activity of neutrophils (Cohen, 2002). The long-term use of corticosteroids has been questioned because of their adverse side effects, particularly in the pediatric population. The trend during the past decade and a half is to use fewer steroids for maintenance therapy (Margarit et al., 1989; Ascher, 1995). Many centers do not now use steroids as part of their long-term regimens. The first report of steroid withdrawal after transplantation was published in 1989 (Margarit et al., 1989). Everson and associates (1999) published a literature review, which demonstrated that greater than 50% to 85% of patients can be withdrawn from steroids without changes in acute rejection episodes, patient survival, or graft survival rates (Stegall et al., 1997). This percentile difference depends on the antirejection agent used for maintenance therapy (e.g., tacrolimus versus cyclosporine or serolimus). Steroid withdrawal is preferable, as it is associated with significantly less hypertension, hypercholesterolemia, and diabetes mellitus, and, moreover, it is less likely to result in cushingoid features and delayed development and obesity in the pediatric patient. Despite controversy over their use in maintenance therapy, corticosteroids remain the first-line agents for the treatment of acute rejection. The response rates vary depending on the organ system and whether the patient is maintained on cyclosporine or tacrolimus (U.S. Multicenter FK506 Liver Study Group, 1994).

Azathioprine

Azathioprine, the imidazole derivative of 6-mercaptopurine, was introduced in the late 1950s and early 1960s. Its mechanism of action is the inhibition of differentiation and proliferation of T and B lymphocytes by blocking DNA and RNA synthesis. The effect is a reduction in the numbers of circulating white cells, both lymphocytes and granulocytes. One notable advantage of this agent is its steroid-sparing effect, allowing lower dosages of steroids to be used with equal efficacy and fewer side effects. The use of this agent is limited, however, by side effects, particularly hematologic and gastrointestinal (GI). Its use may result in as many as 50% of patients exhibiting bone marrow suppression and a profound leukopenia or thrombocytopenia (Cattral et al., 2000). Gastrointestinal side effects include pancreatitis, nausea, vomiting, and hepatotoxicity. Patients are at increased risk for opportunistic infections. An increased risk for malignancy, especially lymphoma, however, remains controversial. The primary pathway of metabolism is inactivation by xanthine oxidase, an enzyme blocked by allopurinol. The recommended dosage of azathioprine is 1 to 2 mg/kg per day. Plasma levels are not monitored for this agent.

Mycophenolate Mofetil

Mycophenolate mofetil (MMF) (CellCept) is a morpholinoethyl ester of mycophenolate. It is well absorbed orally and hydrolyzed to its active form, mycophenolic acid, which acts by competitively inhibiting inosine monophosphate dehydrogenase and hence blocks de novo synthesis of purines, primarily guanine. Lymphocytes, unlike other rapidly replicating cells, depend entirely on this pathway for purine synthesis. Hence, the primary mechanism of action of MMF is the selective inhibition of lymphocyte proliferation. This drug is one of the newer agents introduced in the past 10 years and has been shown to be more efficacious than azathioprine in combination therapy (Fisher et al., 1998). There is also some experimental evidence to suggest that MMF may reduce the risk for chronic allograft rejection, which has been attributed to its antiproliferative activity against B lymphocytes and arterial smooth-muscle cells (Azuma et al., 1995; Schmid et al., 1995). The most common side effects are GI, including nausea, abdominal pain, anorexia, gastritis, and diarrhea. Diarrhea affects as many as 30% of patients but usually responds to a decrease in dosage. MMF also causes leukopenia and thus should be avoided in combination with azathioprine. The usual dosage is 1 to 3 g/day orally in two divided doses. Like azathioprine, blood levels are not monitored with this agent. The antivirals acyclovir and ganciclovir increase MMF levels, and antacid decrease the absorption of MMF (Cohen, 2002).

Calcineurin Inhibitors

Calcineurin inhibitors are the primary immunosuppressives agents that have been developed to date; they include tacrolimus and cyclosporine and are effective by their interaction with calcineurin. The most important cytokine in the immunology of transplantation rejection appears to be IL-2. It is produced through a sequence of events, which commence when a recipient antigen-processing cell comes into contact with the donor cells’ major histocompatibility (MHC) antigens. The donor MHC fragment is processed and placed on the antigen-processing cell surface. When an appropriate recipient T cell is encountered, the T-cell receptor and the donor MHC bind. This initiates a cascade of intracellular enzymatic reactions via phosphorylation, and calcium stores are released, which then combine with calmodulin. This calcium-calmodulin complex then activates calcineurin. Calcineurin appears to be directly involved in the pathway that induces the production of the IL-2 molecule. Cyclosporine and tacrolimus act primarily by binding calcineurin via the cyclosporine-cyclophilin complex or the tacrolimus-FK binding protein complex, respectively. Binding of calcineurin by either of these complexes inhibits its enzymatic action, preventing the dephosphorylation of nuclear factor of activated T cells. This nuclear factor of activated T cells must be dephosphorylated to enter the nucleus, where it is required for IL-2 gene transcription.

Rapamycin

Rapamycin (Sirolimus) is a macrolide antibiotic isolated from the fungus Streptomyces hygroscopicus. It effectively inhibits both B- and T-cell activity (Poon et al., 1996; Poston et al., 1999). Rapamycin is structurally similar to tacrolimus. It uses the same intracellular binding protein as tacrolimus but blocks B- and T-cell activation at a later stage than the calcineurin inhibitors. Rapamycin and cyclosporine appear to act synergistically to inhibit lymphocyte proliferation (Kimball et al., 1991). The oral bioavailability of rapamycin is variable. Like the calcineurin inhibitors, it is metabolized by the cytochrome P450 3A system. The efficacy of rapamycin in solid organ transplantation was initially shown in the renal transplant population (Groth et al., 1999; Kahan et al., 1999; McAlister et al., 2000). Small studies in liver transplant patients have shown rapamycin to be an effective agent when combined with a calcineurin inhibitor (Watson et al., 1999; Trotter et al., 2001). Most of these patients could be maintained on steroid-free regimens. Acute rejection episodes were significantly decreased compared with historical controls (30% versus 70%) (Kahan for the Rapamune U.S. Study Group 2000). A primary role of rapamycin is to facilitate a dosage reduction of calcineurin inhibitor in those patients with evidence of tacrolimus or cyclosporine toxicity (Brattstrom et al., 1998; Groth et al., 1999). The most frequent dosage-related adverse effects include hyperlipidemia, leukopenia, thrombocytopenia, oral ulcerations, and joint pains. Both cholesterol and triglyceride levels can significantly increase and should be monitored while on therapy. Calcineurin inhibitor levels, especially those of cyclosporine, have been shown to significantly increase while on rapamycin therapy and should be closely monitored.

Antilymphocyte and Antithymocyte Globulins

Antilymphocyte globulin (ALG) and antithymocyte globulin (ATG) are produced by extracting immunoglobulins from animals (usually horse or rabbit) that have been immunized with human lymphocytes or thymocytes, respectively. The IV administration of these polyclonal antibodies causes rapid and profound depletion of peripheral lymphocytes. A major limitation of all polyclonal antilymphocyte preparations is batch-to-batch heterogeneity, which results in unpredictable side effects and more importantly, variable efficacy. ALG and ATG are not typically used as first-line agents for immunosuppression. They appear to delay the onset of the first episodes of organ rejection, but the overall rates of rejection are similar to those seen with calcineurin inhibitors (Neuhaus et al., 2000). The focus of this form of therapy is as the primary immunosuppression in patients unable to tolerate calcineurin inhibitors (i.e., because of significant pretransplant renal insufficiency) and in the treatment of steroid-resistant (and possibly OKT3-resistant) rejection. Commonly observed side effects include allergic reactions, serum sickness, fever, and thrombocytopenia, as with OKT3 and other systemically infused immunoglobulins. Cytokine release syndrome (cardiovascular collapse with a hemodynamic profile similar to septic shock, noncardiogenic pulmonary edema, seizures, hyperpyrexia and renal insufficiency) may be seen with the administration of these agents, which is similar to that sometimes seen with OKT3 or any other immunoglobulin. The incidence of lymphoproliferative disease is also increased among patients who have received ALG and ATG.

OKT3

OKT3 (Orthoclone OKT3, muromonab-CD3) is a monoclonal antibody directed against the CD3 complex of the cell membrane of lymphocytes (Fung et al., 1987); it is an antibody specifically directed at the T3 antigen of human T cells—the cells that directly attack the transplanted organ—and it is unlike the polyclonal antibody preparations. IV infusion results in tremendous lymphocyte depletion. Induction with OKT3 has not shown any significant benefit over the calcineurin inhibitors (McDiarmid et al., 1991). Because of its toxicity and the availability of less toxic agents, OKT3 is generally reserved for patients with severe steroid-resistant rejection (Portela et al., 1995; Wall and Adams, 1995). OKT3, ALG, and ATG provide 60% to 90% graft salvage rates for acute rejection in various organ system transplants. The side-effect profile of OKT3 is similar to that of ALG and ATG, including the cytokine release syndrome, infectious complications, and malignancy potential. This protein, like ALG and ATG, should be administered to a patient who is monitered. Lymphocyte and platelet counts must be closely monitored. CMV infection should be anticipated in all patients treated with OKT3 if they have not received CMV prophylaxis.

Interleukin-2 Receptor Antagonists

As discussed earlier, IL-2 is the most noteworthy cytokine known to be involved in the rejection of transplanted solid organs. Although calcineurin inhibitors decrease the amount of IL-2 produced, competitive inhibition by IL-2 receptor antagonists prevents the protein itself from binding to the active lymphocytes. Unlike ALG, ATG, and OKT3, which target the entire lymphocyte population, IL-2 receptor antagonists specifically target the actively dividing cells by binding to the IL-2 receptor’s CD25 moiety, which is expressed only in active cells (Langrehr et al., 1998). The two available IL-2 receptor antagonists are basiliximab and daclizumab. Early studies indicated that these agents need to be combined with calcineurin inhibitors to be effective (Vincenti et al., 1998). These agents should probably be used for induction of immunosuppression (Eckhoff et al., 2000) in those patients at high risk for calcineurin inhibitor–related toxicity. Additionally, they appear to be well tolerated without significant adverse effects. Dosages and timing of administration of these agents vary, depending on the organ system to be transplanted. Moreover, it appears that IL-2 receptor antagonists are needed immediately at the time of the transplantation (immediately before or after reperfusion of the transplanted organ), with a second dose at approximately 4 days in the immediate immunosuppressive induction period.

Belatacept

Belatacept is a fusion protein composed of the Fe fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4, which is a molecule crucial for T-cell costimulation, selectively blocking the process of T-cell activation. It is intended to provide extended graft survival while limiting the toxicity generated by standard immune suppressing regimens, such as calcineurin inhibitors.

In a phase II multicenter study comparing the safety and efficacy of belatacept and cyclosporine A in 218 patients who had undergone renal transplantation with deceased- or living-donor kidneys, Vincenti and colleagues (2005) noted that at 6 months after transplantation, there were no significant differences in the incidence of clinically suspected, biopsy-proved acute rejection between the two treatment groups. In addition, investigators noted that renal function and chronic allograft nephropathy were significantly better in patients receiving belatacept, and the cardiovascular and metabolic endpoints of hypertension, hyperlipidemia, and posttransplantation diabetes were also better in patients receiving belatacept.

Alemtuzumab (Campath-1H)

The use of alemtuzumab (Campath-1H) in organ transplantation goes back to 1986, when Hale and colleagues (1986) in Europe reported on the preliminary results of a pilot study in renal, liver, and pancreas transplant recipients. Alemtuzumab is a humanized immunoglobulin IgG1 monoclonal antibody directed against CD52, a cell-surface glycoprotein expressed on circulating T and B cells and to a lesser extent on natural killer cells, monocytes, and macrophages. It has been suggested that after binding to its target, alemtuzumab causes cell death through complement-mediated cell lysis and antibody-mediated cellular cytotoxicity (Hale et al., 1986; Nuckel et al., 2005; Weaver and Kirk, 2007). Alemtuzumab was approved by the FDA for the treatment of lymphoid malignancies in 1999. It has been used off-label in bone marrow transplantation to prevent graft-versus-host disease and to treat various autoimmune diseases such as rheumatoid arthritis, scleroderma, and multiple sclerosis. Because of its rapid and profound lymphocyte-depleting effects, alemtuzumab was initially used off-label as induction therapy in renal transplantation to allow safe avoidance or minimization of steroid or calcineurin-inhibitor therapy. Retrospective analysis of the OPTN/UNOS database revealed that alemtuzumab induction was associated with a lower rate of acute rejection during the first 6 months after transplantation compared with no induction. Other studies have shown that antibody preconditioning with alemtuzumab without maintenance immunosuppression failed to achieve tolerance in clinical transplantation. Campath-1H also has an associated cytokine-release syndrome, which reportedly has been prevented completely by coadministration of solumedrol (2 mg/kg), Benadryl (2 mg/kg), and other antiinflammatory agents. Most patients who are pretreated still become febrile with the induction dose of the medication. The treatment for this hyperpyrexia is discontinuation of the agent. The usual pediatric induction dose is 0.3 to 0.4 mg/kg infused over 8 hours. Opportunistic infections and malignancies are of grave concern with a potent lymphocyte-depleting agent such as this, but an excessive frequency has not been reported.

Child-Pugh Classification

The Child-Pugh classification is a universal scoring system of the degree of liver failure in patients with cirrhosis. Traditionally, the Child-Pugh class (A, B, or C) has been used as a predictive index for operative mortality rate in adult patients undergoing portosystemic shunting procedures. The estimated 1- and 5-year survival rates are 95% and 75% for patients with Child-Pugh class B, and 85% and 50% for patients with Child-Pugh class C. After the onset of the first major medical complication (ascites, variceal bleeding, jaundice, or encephalopathy), survival rates for these patients are significantly reduced. Variables measured by this system include ascites, encephalopathy, serum albumin, bilirubin, and prothrombin time (PT). Points are then assigned to different degrees of each variable, and the total points are used to assign a grade in the Child-Pugh scoring system (Table 28-16). Although a liver biopsy is often helpful in assessing histologic activity and the amount of fibrosis in patients with chronic hepatitis, it is not essential for the determination of the Child-Pugh class. Until February 2002, the Child-Pugh score was used by transplantation centers to group patients into one of four medical urgency categories. Blood type, patient size, medical urgency and waiting time determined liver allocation.

Pediatric End-Stage Liver Disease Scale

The PELD numerical scale is currently used by UNOS for liver allocation for children less than 12 years old. (PELD replaced the previous status 2B and 3 for pediatric patients, but status 1 is not affected by PELD.) PELD is based on bilirubin, INR, albumin, growth failure, and age when the patient is listed for transplantation, and it is used to calculate a numerical value that is an accurate predictor of 3-month mortality, independent of the complications of portal hypertension and the etiology of the liver disease. The MELD (model for end-stage liver disease) scale is a similar numerical scale ranging from 6 (less ill) to 40 (gravely ill) that is used for patients 12 years old and older. The score indicates how urgently the patient needs a transplant in the next 3 months. The number is calculated from three routine laboratory test results: bilirubin, INR, and creatinine. The measures used are as follows:

Cardiovascular System

Progressive liver failure is characterized by a hyperdynamic circulation with a left ventricular (LV) ejection fraction of greater than 65%, fixed low total peripheral resistance, and a compensatory rise in cardiac output, impaired circulatory reserve, and diminished response to catecholamine infusions. High-risk patients have cardiomyopathy and dysrhythmias, congestive heart failure from fluid and electrolyte imbalances, and moderate to severe pulmonary hypertension.

Systemic vascular resistance is low because of peripheral vasodilation and shunting (cutaneous, splanchnic, intrapulmonary, portopulmonary, lumbrical, and pleural). This profound vasodilation may result from abnormal levels of vasodilator substances, possibly originating in the splanchnic circulation, which would otherwise be cleared by the liver, or from the lack of a substance produced by the liver. The most likely mediators include nitric oxide, tumor necrosis factor-α, and endothelium-derived relaxing factor. Activation of the renin-angiotensin-aldosterone system causes an increase in extracellular fluid volume through salt and water retention, and release of AVP results in a decrease in free-water excretion. Similarly, the sympathetic nervous system is activated in an attempt to cause peripheral vasoconstriction to maintain an adequate MAP. Mixed venous oxygen saturation (Svo₂) measured in the pulmonary artery outflow tract is markedly elevated (usually ≥85%). The increase in Svo₂ presumably results from poor oxygen extraction capacity and correlates somewhat with cardiac index (Jugan et al., 1992; Steib et al., 1993). Yet there is no evidence of tissue dysoxia or increased serum lactate with the patient at rest.

Respiratory System

Cirrhotic patients are predisposed to arterial hypoxemia from intrapulmonary shunting because of capillary vasodilation, restrictive lung disease caused by ascites or pleural effusions, impaired hypoxic pulmonary vasoconstriction, increased pulmonary blood flow, and a rightward shift in the oxygen-dissociation curve resulting from decreased levels of 2, 3-diphosphoglycerate. Respiratory compromise may also result from the hepatopulmonary syndrome (HPS), portopulmonary hypertension, defects in alveolar oxygen diffusion, or pulmonary manifestations of systemic disease (e.g., cystic fibrosis, autoimmune disease, α₁-antitrypsin deficiency). These defects are seemingly compensated for by an increase in Svo₂ and resting cardiac output (Schott et al., 1999; Teramoto et al., 2000). Arterial hypoxemia usually responds to supplemental oxygen and positive pressure ventilation suggestive of a V/Q mismatch. Depressed airway reflexes, delayed gastric emptying, hiatus hernia, and massive ascites increase the risk for aspiration. Pulmonary edema, atelectasis, and pneumonia are also common findings in patients with ESLD.

The frequency of HPS (chronic liver disease, increased alveolar-arterial gradient while breathing room air, and intrapulmonary vasodilation) is reported to be between 4% and 29% (Naeije, 2003; Mazzeo et al., 2004). Patients with liver disease may develop progressive and refractory hypoxemia when abnormal intrapulmonary vascular dilation causes anatomic shunting and diffusion-perfusion abnormalities (Hoeper et al., 2004). The prognosis for patients with HPS is poor, and a mortality rate of 41% within 2 to 5 years has been reported (Krowka et al., 1993). In contrast, up to 20% of cirrhotic patients are at risk of developing portopulmonary hypertension (portal hypertension and increased pulmonary vascular resistance). Severe pulmonary hypertension may cause acute right ventricular failure and sudden cardiac death (Scott et al., 1999). Preoperative therapy with epoprostenol and nitric oxide may improve outcome in this group if right ventricular function is preserved and treatment results in a decrease in pulmonary pressures and vascular remodeling.

Renal System

Renal dysfunction is common in patients with ESLD, and the kidneys are very susceptible to injury and prone to failure. Fluid and electrolyte imbalances are secondary to diuretic therapy, hypoalbuminemia, and portal hypertension causing generalized ascites, progressive edema, hypovolemia, dilutional hyponatremia, and hypokalemic metabolic alkalosis resulting from renin-aldosterone activation. Three main mechanisms, singularly or in combination, contribute to renal insufficiency: prerenal causes, acute tubular necrosis, and hepatorenal syndrome. Renal insufficiency not only complicates the management of liver failure but, more importantly, may increase patient mortality. Thus, it is important to evaluate and treat reversible causes of renal insufficiency (Box 28-4). Renal function is often difficult to assess in these patients because reduced muscle mass and hepatic synthesis of creatine reduces the serum creatinine level. Creatinine clearance will overestimate the GFR.

Prerenal azotemia is most commonly associated with aggressive use of diuretic therapy in the treatment of ascites. With a decreased effective arterial volume, patients are more susceptible to the volume depletion effects of diuretics and large volume paracentesis without adequate intravascular volume replacement. As with other types of prerenal azotemia, the urine sodium level is low (<10 mEq/L), with a fractional excretion of sodium (FENa) of less than 1%. This type of renal failure is amenable to careful volume replacement.

The kidneys in patients with liver failure are also at increased risk for developing acute tubular necrosis (ATN) as a result of decreased renal perfusion. This decreased perfusion is a consequence of a relative decrease in central blood volume caused by splanchnic pooling, which activates secretion of vasopressin, in combination with other compensatory mechanisms attempting to restore MAP, such as increased sympathetic tone and renin-angiotensin activity. Renal perfusion is further compromised because prostaglandin synthesis is reduced in advanced liver disease. Prostaglandins are potent renal arteriolar vasodilators (Govindarajan et al., 1987; Claria and Arroyo, 2003). Hence, tubular function is much closer to an ischemic threshold in patients with liver failure. This low ischemic threshold renders the kidneys more susceptible to nephrotoxic drugs such as IV contrast dye or aminoglycosides. Additionally, in the patient with tense ascites, renal cortical perfusion may also be diminished as a result of elevated intraabdominal pressure. Urine sodium in this setting is usually greater than 20 mEq/L, with a FENa of greater than 1% (Epstein, 1985). Treatment should be directed at minimizing additional renal injury, optimizing renal perfusion, and maintaining urine output, with some form of dialysis possibly introduced until the ATN resolves. This usually occurs within 10 to 14 days. It is not uncommon, however, for the hepatorenal syndrome to become superimposed once the patient develops ATN.

The most consequential form of renal dysfunction is the hepatorenal syndrome, and it has a very poor prognosis. It is characterized by a rapid deterioration in renal function associated with profound sodium retention and low urinary sodium excretion. It is usually precipitated by a major physiologic event, such as GI hemorrhage, sepsis, or surgery. It is differentiated from prerenal azotemia by the lack of responsiveness to volume expansion. The pathogenesis is severe renal vasoconstriction with absence of renal cortical blood flow. Interestingly, this vasoconstriction is reversible if the kidney is transplanted into a host with normal hepatic function (Koppel et al., 1969). This form of renal failure requires dialysis to sustain life, but it may be reversible with liver transplantation (Iwatsuki et al., 1973).

Hematologic Complications

Anemia, thrombocytopenia, and coagulopathy are the expected findings in the patient with liver failure. Anemia is usually a result of bone marrow suppression, vitamin deficiency, hemorrhage, and diminished erythropoietin production caused by renal insufficiency. Thrombocytopenia (platelet count < 100,000/mm³) is seen in 70% of patients with liver disease (Kang et al., 1985) and is primarily a result of diminished thrombopoietin production and portal hypertension with platelet sequestration in the spleen (Kaushansky, 1995; Martin et al., 1997). However, bone marrow suppression, abnormalities in platelet metabolism or autoimmune causes may also be contributing factors (Peck-Radosavljevic, 2000). Impaired platelet aggregation and clot retraction caused by qualitative platelet defects are also seen in patients with liver disease and renal failure.

The tissue factor pathway of coagulation is classically assessed by measuring PTT and PT. The liver is the main site of synthesis of all coagulation factors except von Willebrand’s factor, which is produced primarily in the vascular endothelium. Failure of bile salt secretion results in poor absorption of vitamin K, which is a cofactor necessary for the posttranscriptional γ-carboxylation and activation of factors II, VII, IX, and X (Table 28-17). In cirrhotic patients, the levels of fibrinogen and factor VIII are usually supranormal, and the production of all other clotting factors is diminished. Additionally, approximately 80% of patients with liver failure produce an abnormal fibrinogen molecule (dysfibrinogenemia) (Martinez et al., 1978; Cunningham et al., 2002). Control of coagulation therefore depends on the balance of hepatic synthesis of clotting factors and the clearance of activated clotting factors, plasminogen activators, and fibrinolytic proteins.

Neurologic Complications

Hepatic encephalopathy is a frequent metabolic complication of acute or chronic liver disease. The neuropsychiatric abnormalities are often reversible, with the clinical presentation ranging from subtle personality changes to frank coma. Neuromuscular symptoms include tremor, hyperreflexia, and decerebrate posturing. The three theories regarding the pathogenesis of hepatic encephalopathy are (1) ammonia toxicity with accumulation of toxins in the brain, (2) an alteration in plasma amino acid composition with accumulation of false neurotransmitters, and (3) an increase in neuroinhibitory substances, such as manganese, monoamines, and endogenous opiates. Various studies have supported aspects of each hypothesis, yet none has been conclusively established. In patients who have died in hepatic coma, neuropathologic findings occur in the astrocytes rather than in the neurons. Positron emission tomography studies show decreased glucose use in the cerebral cortex, which may explain some neuropsychiatric abnormalities (Butterworth, 1996).

Forty percent of ammonia is generated in the intestine from ingested nitrogenous substances, and it is subsequently metabolized in the liver into urea, which is excreted through the kidneys and into the colon. With liver failure and portosystemic shunting, ammonia, which is a known neurotoxin, accumulates and readily diffuses into the brain, where it exerts its neurotoxicity. Arguments against ammonia being the sole factor in the pathogenesis have been based on (1) the lack of a strong correlation between blood ammonia levels and the degree of hepatic encephalopathy, (2) the presence of this condition in the absence of elevated ammonia levels, and (3) the neuroexcitatory effects of low ammonia concentration. Other metabolic by-products, such as mercaptans and short-chain fatty acids, have also been implicated.

With progressive liver failure, the ratio of branched-chain amino acids to aromatic amino acids decreases. These aromatic amino acids cross the blood-brain barrier and may competitively inhibit normal neurotransmitters and favor the generation of false neurotransmitters (e.g., octopamine) that have an inhibitory effect on cerebral function.

Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the CNS, regulates the chloride channel. It has been suggested that elevated ammonia levels enhance GABA-ergic neurotransmission and synergistically augment the action of benzodiazepine receptor agonists (Basile and Jones, 1997). This theory is supported by the fact that hepatic encephalopathy can at times be improved by the benzodiazepine receptor-antagonist flumazenil.

Among the multiple precipitating factors of hepatic encephalopathy are azotemia, drugs (sedatives, tranquilizers, analgesics), GI bleeding, excess dietary protein, metabolic alkalosis, infection, and constipation (Abou-Assi et al., 2001). Treatment consists of reducing dietary protein, avoiding sedatives, administering antibiotics such as neomycin or Bactrim, administering lactulose (which converts ammonia to nonabsorbable ammonium and modifies the colonic flora), correction of hypokalemia, discontinuation of diuretics, treating infection, and volume expansion.

Endocrine dysfunction is common in ESLD. Oversecretion of growth hormone and glucagon leads to peripheral and hepatic insulin resistance and impaired glucose metabolism, with lipids as a preferred energy substrate. Hypoglycemia is an ominous sign indicative of depletion of glycogen stores in the liver and survival is limited to days without IV glucose supplementation and transplantation. It is often seen with infections or sepsis.

Urea-Cycle Disorders

Urea-cycle disorders are one of the common inborn errors of metabolism that are clinically cured by liver transplantation (Morioka et al., 2005). As the urea cycle is the final pathway for the elimination of nitrogen. Enzymatic defects or errors in the pathway lead to the accumulation of nitrogen as ammonia, alanine, glutamate, and other intermediate metabolites. The urea cycle contains five enzyme systems, and the clinical manifestations depend on the enzyme that is deficient (Fig. 28-2). These enzyme deficiency syndromes are carbamoyl phosphate synthetase I deficiency, ornithine transcarbamylase deficiency (OTCD), argininosuccinate synthetase deficiency (citrullinemia), argininosuccinate lyase deficiency, and N-acetylglutamate synthetase deficiency. OTCD is the most common urea-cycle disorder, with a prevalence of 1 in 40,000 live births, and it is inherited as an X-linked, partially dominant chromosomal defect. Ornithine transcarbamylase is a mitochondrial enzyme that catalyzes the conversion of ornithine (the product of carbamoyl phosphate synthetase–catalyzed ammonia and bicarbonate) and carbamylphosphate to citrulline. OTCD thus results in the accumulation of ammonia, carbamylphosphate, and glutamate, with diminished production of citrulline, arginine, and urea. Because of the X-linked, partially dominant inheritance of OTCD, the phenotypical expression of OTCD is varied. In the severe form, which affects homozygous males, hypothermia, lethargy, and vomiting follow a 24- to 72-hour asymptomatic period. Symptoms are progressive and severe and are related to accumulation of glutamine and ammonia and secondary cerebral edema. In heterozygous females, the expression is more varied and can range from neonatal expression to clinically imperceptible disease. Accumulation of ammonia is exacerbated by protein breakdown at times of stress (surgery, sepsis, dehydration, anesthesia) or fasting, and also with the ingestion of high-protein foods or parenteral nutrition. Anesthesia management in these children focuses on avoidance of catabolic states through infusion of physiologic fluids containing at least 10% dextrose. Avoidance of emotional stress is imperative, with liberal use of perioperative benzodiazepines and analgesics. Hypothermia should be prevented with the use of warm room temperatures, irrigation, and warming blankets. Some centers also use continuous intraoperative IV infusions of sodium benzoate (300 to 500 mg/kg per day) for nitrogen binding. OTCD may also be independently associated with a hypercoagulable state, with documented thrombotic complications in four children (Venkateswaran, 2009).

FIGURE 28-2 A, Urea cycle, showing the reactions by which excess nitrogen in the form of ammonia is converted to soluble urea, using l-ornithine as a recyclable carrier. B, Pathway of branched-chain amino acid (BCAA) catabolism. Note that the branched-chain organic acids are derived from the BCAAs by deamination, and the site of the defect in maple syrup urine disease (MSUD) is the dehydrogenase complex. The asymmetry of the β-carbon of isoleucine and the reversibility of the keto-enol interconversion give rise to alloisoleucine, which is virtually pathognomonic for MSUD.

(From Khanna A, Hart M, Nyhan WL, et al: Liver transplantation in maple syrup urine disease, Liver Transplant 12:876, 2006.)

Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is an inborn error of amino acid metabolism caused by the autosomal recessive–mediated deficiency in branched-chain α-ketoacid dehydrogenase (BCKD) activity. BCKD is the second enzyme in the pathway used in the degradation of the branched-chain amino acids leucine, isoleucine, and valine (Morton et al., 2002) (see Fig. 28-2). The pathophysiology of MSUD is primarily explained by the accumulation of leucine in the plasma and in the organs. Similar to the urea-cycle disorders, severe metabolic decompensation is associated with catabolism of tissue proteins at times of starvation and stress. The disease usually manifests within 48 hours of birth with ketonuria, irritability, and dystonia that progresses to seizures and coma by the fourth day of life (Felber et al., 1993). Diagnosis is confirmed by testing for the presence of branched-chain 2-ketoacids in the urine and by quantification of branched-chain amino acids in the plasma. Children are treated with dietary restriction of branched-chain amino acids and avoidance of catabolic states. Despite strict dietary control, severe metabolic crises can still develop suddenly during intercurrent illnesses and can be associated with life-threatening cerebral edema. In addition to facing the dangers of acute metabolic decompensation, patients with MSUD often suffer from neurocognitive disorders, probably from imbalances of branched-chain amino acids in the brain. Because of their protein-restricted diet, MSUD patients can also develop essential-amino-acid deficiencies, resulting in immunodeficiency, growth failure, and global developmental delays. Patients undergoing liver transplantation for MSUD are carefully selected, and successful outcomes depend on a multidisciplinary approach to their management in the perioperative period (Strauss, 2006). A careful neurologic examination should be documented before sedation to serve as a baseline, and a careful history of past metabolic crises and neurologic deficits should be obtained. Baseline levels of branched-chain amino acids should be recorded, and, if they are excessive, transplantation should be deferred and medical treatment initiated. Like patients with urea-cycle disorders, patients with MSUD cannot be fasted without catabolic consequence. In addition, specialized total parenteral nutrition (TPN) should be used that include concentrated dextrose infusions. MSUD patients should never receive hypotonic infusions, and plasma osmolarity should be carefully monitored and kept in the normal range. Perioperative sedation and analgesia should be optimized to avoid catabolism, and physiologic stress should be kept to a minimum (Kahraman, 1996; Fuentes-Garcia, 2009). Leucine levels are generally followed after reperfusion of the liver and daily after the transplantation. Patients are immediately fed an unrestricted diet or are given enteral feedings with standard protein compositions.

Alagille’s Syndrome

Alagille’s syndrome (AS) is an autosomal disorder characterized by bile duct paucity, cholestasis, and progression to cirrhosis, requiring transplantation in 30% of patients. The syndrome is also associated with characteristic facial features, ocular manifestations, vertebral anomalies, and pancreatic insufficiency. Renal disease is another important feature of this syndrome with structural and functional disorders in up to 50% of patients including renal artery stenosis, dysplastic or ectopic kidneys, and tubulointerstitial nephropathy. Idiopathic intracranial hemorrhage occurs in up to 15% of patients and is often fatal. Patients with AS should be screened with magnetic resonance angiography (MRA) of the head prior to transplantation to identify any cerebral vascular malformations. Cardiac anomalies are also a component of AS, with the most common manifestation being central or peripheral pulmonary arterial stenoses. Up to 24% of patients also have associated intracardiac anomalies. Tetralogy of Fallot, aortic coarctation, septal defects, patent ductus arteriosus, pulmonary atresia and pulmonary stenosis have also been reported with AS (Perlmutter and Shepherd, 2002). In patients with right ventricular outflow obstruction, the severity of the outflow gradient is a major factor in the perioperative morbidity and mortality.

Wilson’s Disease

Wilson’s disease (hepatolenticular degeneration) is an autosomal recessive disorder characterized by progressive or acute liver decompensation in the first 2 decades of life, although its appearance later with neuropsychiatric symptoms is also common. Wilson’s disease represents a mutation in the ATP7B gene, which causes a progressive accumulation of copper in the liver as a result of impaired copper excretion into the bile. As time passes, the capacity of the liver to accumulate copper is exceeded, and copper is released into the circulation. In addition to liver decompensation, copper accumulation also affects the CNS, with a myriad of neuropsychiatric symptoms. Severe Coombs-negative (non-immune-mediated) intravascular hemolysis is frequent and is the presenting symptom in up to 15% of patients. Arrhythmias, autonomic dysfunction, and LV hypertrophy are seen in up to 25% of patients (Hlubocká et al., 2002).

α₁-Antitrypsin Deficiency

α₁-Antitrypsin deficiency (A1AT) is a relatively common autosomal recessive disorder. It is a serine protease inhibitor that inhibits destructive neutrophil proteases, and it limits the destructive effects of neutrophil effectors during times of inflammation. In the homozygous form, there is a 90% reduction in circulating concentrations of A1AT. α₁-Antitrypsin has a reported incidence of liver involvement in 10% to 20% of patients, primarily those who are PIZZ homozygotic (Psacharopoulos et al., 1983). The incidence of this phenotype is 1 in 7000 in the United States and 1 in 2000 in Scandinavia (Schwarzenberg and Sharp, 1990). Males are affected more frequently than females. Some 10% to 20% of PIZZ individuals develop neonatal cholestasis, and jaundice is often the first sign of this disease. The liver disease associated with A1AT deficiency can become clinically apparent at any time from infancy to late adulthood. Of note for anesthesiologists, patients with homozygous A1AT deficiency develop progressive emphysematous lung disease; however, these changes are generally not severe until well into adulthood.

Preoperative Evaluation

Risk assessment of the patient scheduled for OLT is still in its evolutionary stage. The primary focus for the anesthesiologist is to evaluate the whole patient for systemic manifestations of ESLD as well as predictable disease-specific extrahepatic manifestations (such as pulmonary involvement with cystic fibrosis).

Cardiovascular Evaluation

Cardiac evaluations of pediatric candidates for OLT should be tailored to the underlying cause of cirrhosis. Inherited metabolic liver disorders rank second behind biliary atresia as an indication for OLT in children, so possible myocardial involvement should be considered in patients with oxalosis, glycogen storage disease types III and IV, Gaucher’s disease, Niemann-Pick disease, Wilson’s disease, neonatal iron storage disease, and amyloidosis. The physical examination and diagnostic work-up should focus on cardiac auscultation, the presence or absence of cyanosis (arterial oxygen saturation SpO₂ and Pao₂), or clubbing and transthoracic echocardiography. Detection of a cardiac anomaly may then require cardiac catheterization.

Cardiac function in adults with cirrhosis has been extensively investigated, but there is little information available on children. A study of 22 children with cirrhosis compared with a control group of healthy age- and gender-matched children (mean age, 4.1 ± 3.5 years) reported that pediatric OLT candidates have normal LV systolic function unless their heart was primarily involved in the underlying disease. In advanced liver failure, LV systolic function may be impaired. These children also had increased systolic LV posterior wall thickness, which may reflect LV hypertrophy and impaired diastolic function. LV ejection fraction is usually normal or increased at rest in adults with cirrhosis unaccompanied by ascites (Grose et al., 1995; Laffi et al., 1997). The presence of ascites adversely affects cardiac function in adults (Valeriano et al., 2000). In contrast, most pediatric patients with ascites have normal LV systolic function. Cyanosis is not a reliable sign of hypoxemia in children because of changes caused by crying, anemia, and jaundice. Clubbing in patients with chronic liver disease is a common finding, with a prevalence ranging from 23% to 32% (Ozcay et al., 2002). Given the physiologic stresses inherent in liver transplantation surgery, cardiac problems may emerge perioperatively that contribute to significant morbidity and mortality in patients with cirrhosis and mild or latent cardiomyopathy (Myers and Lee, 2000).

Pulmonary Evaluation

Patients with FHF have varying degrees of pulmonary impairment, including normal Pao₂ and reduced diffusion capacity of the lung for CO (D_Lco), significant arterial hypoxemia, HPS, portopulmonary hypertension, and preexisting lung disease. It is not known whether the high-risk pediatric patient scheduled for liver transplantation surgery can be identified by obtaining values for forced expiratory volume at 1 second (FEV₁), D_Lco, and Pao₂. Investigative studies include chest radiography, pulmonary function studies, a high-resolution CT lung scan, contrast echocardiography, a technetium-99m radionuclide scan, arterial blood gas measurements, and a multiple inert gas elimination technique (MIGET) study when indicated.

Cirrhosis affects the pulmonary circulation, lung parenchyma, and pleural spaces. Reduced alveolar-capillary diffusion (D_Lco) may be seen in the absence of significant hypoxemia, especially in patients with hepatitis C virus (HCV) cirrhosis. This anatomic derangement of the alveolar-capillary membrane worsens with disease progression, with the measured D_Lco becoming abnormal at less than 80% of predicted value. A reduced diffusion capacity may persist up to 15 months after transplantation (Ewert et al., 1999). Of interest, the Hepatitis C Association supports a no-smoking policy for teens and adults, as smoking has been determined to be an independent risk factor associated with elevated ALT levels among anti-HCV-seropositive patients (Wang et al., 2002; Hezode et al., 2003).

Renal Evaluation

Renal dysfunction in conjunction with worsening hepatic function is common. Acute renal failure requiring hemodialysis is a strong predictor of mortality in these patients. Bartosh and colleagues (1997) reported abnormal renal function in one third of children after liver transplantation, with acute renal failure requiring dialysis (in 6.2%) being a predictor of a high mortality rate (85%). The etiology of renal insufficiency in the patient with ESLD is usually multifactorial. Possible causes include hepatorenal syndrome, disturbances of salt and water clearance, acute tubular necrosis, renal pathology associated with the underlying liver diseases, and diminished intravascular volume causing prerenal azotemia. Exposure to nephrotoxic drugs such as IV contrast dyes, aminoglycosides, or nonsteroidal antiinflammatory agents may also contribute to ATN.

Urine sodium handling is an important variable during evaluations. Both prerenal azotemia and hepatorenal syndrome are characterized by normal urinary sediment, very low urine sodium concentrations (<10 mEq/L), azotemia, and oliguria; it is therefore important to exclude hypovolemia. Specifically, hepatorenal syndrome does not respond to a fluid challenge with diuresis, whereas the expected response in the patient with prerenal azotemia is diuresis and a subsequent decrease in the serum creatinine and urea nitrogen levels. ATN tends to be salt wasting at its initial presentation, with urine sodium concentrations characteristically greater than 20 mEq/L. An important diagnostic test is the FENa, which also aids in the distinction between these two disease processes (FENa ≤ 1% for HRS and prerenal azotemia, and greater than 1% for ATN). Obtaining an accurate GFR using creatinine clearance rate values in patients with cirrhosis and ascites may give spurious results, as GFR measurements may range from high values to those diagnostic of end-stage renal disease despite the presence of a normal serum creatinine level (Papadakis and Arieff, 1987).

Renal ultrasonography is a simple (noninvasive), useful adjunct in the evaluation of azotemia. Kidney size and structural abnormalities should be ascertained for evidence of obstructive uropathy. If a renal biopsy demonstrates irreversible renal disease, a combined liver and kidney transplantation should be considered.

Prerenal azotemia caused by hypovolemia usually resolves with judicious volume replacement. ATN is usually self-limited, with resolution in 4 to 6 weeks with appropriate support. However, the hepatorenal syndrome is usually not reversible without liver transplantation (Gonwa et al., 1989).

Venovenous Bypass

The routine use of VVB during the anhepatic phase of OLT, with or without preservation of the cava, remains controversial. In early experiments of OLT in a noncirrhotic dog model, it was discovered that clamping of the portal vein or IVC resulted in death of the animal within 30 minutes (Shaw et al., 1985). Although it was later found that most patients can tolerate caval and portal vein clamping remarkably well, Shaw and colleagues (1984) reported a 10% intraoperative mortality due to hemodynamic instability in adults during the anhepatic phase. Therefore, a bypass system was developed consisting of heparin-bonded tubing and a centripetal-vortex pump, allowing cannulation of the femoral and portal veins and diversion of mesenteric and IVC blood to the SVC through the subclavian or axillary veins (Griffith et al., 1985) (Fig. 28-5). There are no published randomized clinical trials of specific outcomes to evaluate its potential benefits.

FIGURE 28-5 This technique was developed to augment cardiac output and diminish vascular congestion during the anhepatic stage of the surgery. Note the placement of the cannulas, joined by a connector, into the portal vein and the femoral veins. Blood drained from the splanchnic and systemic venous systems is then returned to the right heart through the axillary vein with the aid of a pump.

(From Kang Y, Gelman S: Liver transplantation. In Gelman S, editor: Anesthesia and organ transplantation, Philadelphia, 1987, Saunders, pp 139–185.)

It is difficult to use VVB in patients weighing less than 40 or 45 pounds (~20 kg) (Shaw et al., 1984, 1985). The prerequisite VVB blood flow is usually 20% to 40% of the cardiac output, or greater than 1 L/min (Griffith et al., 1985). As patients are not heparinized, the extremely low-flow states (<500 to 700 mL/min) that result in children weighing less than 20 kg would predispose to almost certain formation of emboli. Despite these findings, VVB still has some specific value in pediatric liver transplantation—notably in larger children with FHF or in older pediatric recipients who are being used as donors for living-donor domino transplantations.

Induction and Maintenance of Anesthesia

Liver transplantation has essentially become a semiurgent or elective procedure. The recipient is premedicated with oral, IV, or intranasal midazolam. In the operating room, standard monitors are placed and the patient is preoxygenated. Patients without serious cardiac disease or multisystem organ failure can tolerate routine induction of anesthesia followed by endotracheal intubation. Rapid-sequence IV induction includes atropine (0.01 to 0.02 mg/kg); a sedative hypnotic agent using thiopental (3 to 5 mg/kg), propofol (2 to 5 mg/kg), etomidate (0.2 to 0.3 mg/kg), or ketamine (1 to 2 mg/kg); and rocuronium (1.0 mg/kg) or succinylcholine (1 to 2 mg/kg). The airway is secured with an oral endotracheal tube (preferably cuffed) with tincture of benzoin and adhesive tape. Placement of an uncuffed tracheal tube of insufficient diameter may result in inadequate alveolar ventilation (especially as chest compliance is reduced during surgery by upper abdominal retraction), tissue edema of the lung parenchyma, surgeons accidentally leaning on the chest wall, and placement of a large liver graft. Additionally, the postoperative risk for silent aspiration must be considered.

Succinylcholine has traditionally been used for intubation in pediatric patients at risk for aspiration. Today, this practice is controversial because of its black-box warning. Because it is difficult to identify which patients are at risk, it is recommended that the use of succinylcholine in children should be reserved for emergency intubation or for when immediate securing of an airway is necessary, as succinylcholine has a faster onset (30 to 60 seconds) than other muscle relaxants. Liver disease, especially if chronic and severe, may be associated with decreased plasma levels of pseudocholinesterases, which will result in prolongation of the duration of action of succinylcholine or drugs requiring ester hydrolysis for degradation (Khoury et al., 1987). However, this effect is of little clinical significance when one considers the duration of perioperative ventilation and the dilutional effect of blood replacement during massive intraoperative bleeding.

Preoperative hyperkalemia may be seen in patients with episodes of acute rejection, sepsis, or poor renal function, or in those taking oral cyclosporine who have chronic rejection or hepatic artery thrombosis. Administration of succinylcholine may increase the serum potassium concentration by 0.5 to 0.7 mmol/L, predisposing the patient with already high serum potassium levels to cardiac arrhythmias and hemodynamic instability. ECG abnormalities and arrhythmias typically do not appear until the serum potassium level is greater than 6.5 mEq/L. Common ECG signs include widened QRS, peaked T-waves, prolonged PR interval, loss of P waves, and atrial systole. ST-segment elevation may mimic acute myocardial infarction. First-degree block may ultimately lead to complete heart block. Late signs include prolonged QRS complex that can lead to sine wave ventricular arrhythmia, ventricular fibrillation, or asystole. Treatment for succinylcholine-induced hyperkalemia focuses on direct cardiac antagonism, intracellular shift, and removal of potassium from the body. Arrhythmia and hypotension are treated with either calcium gluconate or calcium chloride. Intracellular shifting of potassium can be accomplished by administering sodium bicarbonate, glucose, and insulin and hyperventilation (Paco₂, 25 to 30 mm Hg). Kayexalate, furosemide, peritoneal dialysis, or hemodialysis can decrease the total body potassium level.

Alternatively, using a relatively large dosage of a nondepolarizing muscle relaxant (e.g., rocuronium) permits securing the airway rapidly without placing the patient at risk for hyperkalemia. Cisatracurium is the ideal drug for patients with end-stage liver or kidney disease, as it undergoes spontaneous breakdown at physiologic temperature and pH (Hoffmann elimination), as well as ester hydrolysis. However, the dosage required for a rapid onset of action may result in hypotension. In patients with hepatorenal syndrome, nondepolarizing muscle relaxants should be administered cautiously and titrated to effect. Muscle relaxants requiring significant renal excretion include pancuronium (40%), doxacurium (30%), and pipecuronium (38%). Vecuronium and pancuronium also have 3-hydroxy metabolites, which accumulate in renal failure. The 3-hydroxy metabolite of vecuronium is 50% as potent as the parent compound, and that of pancuronium has two-thirds the potency of the parent compound. Muscle relaxants that are metabolized in the liver include pancuronium, vecuronium, rocuronium, and pipecuronium. Vecuronium and rocuronium also have significant biliary excretion. Pancuronium has an increased volume of distribution, prolonged elimination half-life, and decreased plasma clearance in patients with cirrhosis. Therefore, these patients may need more pancuronium initially to achieve muscle relaxation, and they have a prolonged recovery of blockade between doses (Duvaldestin et al., 1978). In patients with biliary obstruction, the initial dosage of pancuronium required is unchanged, but the duration of action of each dose is similarly prolonged (Duvaldestin et al., 1978). This may be advantageous because the operative procedure is lengthy and ventilation is usually required for at least 24 hours postoperatively.

Following induction, the patient is positioned on the operating table supine with the arms abducted and elbows flexed. It is essential to keep the patient covered, warm, and dry. Strategies include the use of a warming blanket, heated humidified gases, or IV fluid warmers; wrapping the extremities; mylar foil wrapping; and use of a thick cotton mattress pad below with a U-shaped surround Bair Hugger forced-air warming device. Care should be taken to avoid stretch injury of the brachial plexus or pressure necrosis of the occiput, ears, heels, sacrum, or elbows. After the induction of anesthesia, additional monitoring is established, using end-tidal CO₂, rectal and esophageal temperature probes, an esophageal stethoscope, an indwelling urinary catheter, a peripheral nerve stimulator, and systemic arterial and CVP cannulas. Access to arterial pressure monitoring above the diaphragm is ideal because cross-clamping of the abdominal aorta may be necessary during the hepatic arterial anastomosis. A femoral arterial catheter can also be used during surgery if there is concern about the accuracy of the radial arterial blood pressure (Kamath et al., 2001). One or two additional large IV cannulas (preferably 20- or 18-gauge) are then inserted in the upper extremities, either percutaneously or by surgical cutdown. The use of VVB in larger children may preclude use of the left arm for venous access. If vascular access in the arms is difficult to obtain, the lower extremities may be used, with the understanding that during the anhepatic stage, venous return to the heart depends on collateral flow or VVB. A central venous catheter is placed in the external or internal jugular vein. In smaller children, the surgeon will often insert a Hickman catheter (large-bore, double-lumen central venous line). The use of a sheath-type catheter in larger children allows the rapid infusion of large volumes of blood components and, in rare circumstances, the insertion of a flow-directed, balloon-tipped pulmonary artery catheter. Technical difficulties in placing a pulmonary artery catheter and subsequent displacement or migration by surgical maneuvers generally preclude its routine use in pediatric patients.

The patient is ventilated with a tidal volume and respiratory rate adjusted to maintain a normal end-tidal CO₂ and arterial CO₂ level of 35 to 40 mm Hg. Tidal volume and minute ventilation can be improved by using a pressure-limited mode. Air oxygen is used with an inspiratory oxygen concentration sufficient to maintain adequate oxygenation. A PEEP of 5 cm H₂O is routinely added because progressive atelectasis is common. Nitrous oxide is avoided because of its sympathomimetic effects, its propensity to cause bowel distention (which may make surgical exposure and closure of the abdomen difficult), and its limiting effect on increasing the inspiratory concentration of oxygen.

During anesthesia, all factors inducing arterial hypotension should be avoided. General anesthesia and surgery decrease hepatic blood flow and jeopardize oxygen supply to the liver. Intraoperative reductions in the arterial blood pressure and cardiac output decrease portal blood flow. Contributing factors include anesthesia drugs (inhalational anesthetics, vasodilators, β-blockers, α-1-agonists, histamine receptor-2 (H₂) blockers, and vasopressin), hypovolemia, ventilatory mode, hypoxemia, hypercarbia, and acidosis. Surgical manipulation in the right upper quadrant can reduce hepatic blood flow up to 60% from sympathetic activation or direct compression of the vena cava and splanchnic vessels. Compensatory vasodilation of the hepatic artery in response to decreased portal inflow is diminished by volatile anesthetic agents in a dosage-related manner (and absent in a denervated liver), and consequently blood flow becomes pressure dependent. Isoflurane has the least detrimental effect on hepatic blood flow. A simultaneous decrease in the liver’s metabolic demand tends to balance the oxygen supply-uptake ratio. A study of hepatic circulation in pigs during surgical stress and anesthesia suggested that fentanyl and light isoflurane provided adequate hepatic oxygen supply, whereas anesthesia with concentrations of isoflurane that decreased blood pressure more than 30%, or with halothane in any concentrations studied, resulted in inadequate hepatic oxygen supply (Gelman et al., 1987). Matsumoto and colleagues (1987) examined the effects of various anesthetic agents on hepatic oxygen supply and hepatic oxygen consumption in the presence of hypoxia. Their results showed that during exposure to mild hypoxia, a dosage of isoflurane less than the minimum alveolar concentration (sub-MAC) maintained the relation of hepatic oxygen supply to hepatic oxygen consumption better than thiopental, halothane, or enflurane.

When administering drugs to patients with chronic liver disease, all dosages should be decreased and carefully titrated until the desired effect is achieved. Current practice is to administer isoflurane alone or in combination with small dosages of fentanyl. The anesthesia management protocol used at the Children’s Hospital of Pittsburgh, and the anesthesia management problems encountered during the four stages of the surgery, can be found online at www.expertconsult.com.

Cardiovascular Changes

During stage I, hypotension results from major fluid shifts, bleeding, and ionized hypocalcemia (Jawan et al., 2003). Transient decreases in MAP are not unusual in this stage and result from surgical manipulation of the liver and compression of the IVC, which transiently preclude venous return to the heart. Drainage of ascites may result in hypotension if the patient is not adequately hydrated prior to incision of the peritoneum. Factors contributing to blood loss include adhesions from prior operations, coagulopathy (factor deficiency, low platelet count, abnormal fibrinogen, or disseminated intravascular coagulation), portal hypertension and collateral venous circulation, and lack of surgical hemostasis (especially a laceration to the IVC). Placement of the suprahepatic caval clamp may be associated with arrhythmia and hypoxemia because of acute right ventricular outflow tract obstruction, as the pericardium and a portion of the RV may be included in the clamp. Hypotension that is unresponsive to IV pressors should raise suspicions of absolute or relative hypovolemia (limited preload caused by vascular clotting or torsion of the liver on its vascular pedicle), acidosis, sepsis, or vasoparesis.

During stage II, classic OLT requires a trial of portal vein and IVC clamping. The hemodynamic response is characterized by a decrease in cardiac output, CVP, and PAP and compensatory increase in heart rate and SVR (Eyraud et al., 2002). Hemodynamic instability may result from decreased venous return (modified by VVB or piggyback technique) and insufficient physiologic compensation by the patient for this acute change. Therapeutic strategies include colloid or crystalloid boluses, and vasopressor support with dopamine or norepinephrine (phenylephrine or epinephrine). The goal is to maintain the lowest filling pressures compatible with an acceptable MAP in anticipation of an increase in PAP with removal of the caval and portal vein clamps. Pulmonary hypertension may result because of an increase in venous return from the gut and lower extremities and reactive changes in PVR with the release of vasoactive hormones that are recirculated systemically. The donor liver is flushed with crystalloid or colloid, or by backwashing (backflushing) the liver. The procedure for backwashing involves insertion of a red rubber cannula into the recipient/donor IVC, and then removal of the clamp from the portal vein allows washing of the liver with autologous blood retrograde from the portal vein through the donor liver, exiting through the cannula into a stainless steel graduated cylinder. If the patient become immediately and dramatically hypotensive, the surgeon must be notified immediately. Hypotension associated with this maneuver can be ameliorated with the prophylactic administration of phenylephrine or epinephrine boluses, gentle fluid administration, or transfusion of packed RBCs if the hematocrit is low. The elimination of air bubbles, hyperkalemic preservation solution, hormones, or other “evil humors” has been credited for decreasing the incidence, in adult patients, of subsequent reperfusion syndrome that may occur with reperfusion of the liver (Fukuzawa et al., 1994). The goal for warm ischemia time is usually less than 60 minutes, so managing hypotension and preparing for reperfusion occurs over a relatively short period. Reactivation of HCV has been shown to be less if the warm ischemia time can be kept under 35 minutes, which shortens the target time for completing this portion of the operation even further (Clavien et al., 2004).

During stage III, profound hemodynamic instability may occur immediately after graft reperfusion. This instability includes severe hypotension, bradycardia, supraventricular and ventricular arrhythmias, variable cardiac output, and occasionally cardiac arrest (0% to 0.5%). These changes are caused by recirculation of the residual cold, acidotic, hyperkalemic preservation solution from the donor liver directly into the recipient’s heart. The incidence of this postreperfusion syndrome (defined as a decrease in MAP and heart rate > 30% from baseline for at least 1 minute within 5 minutes of reperfusion) in adults may be as high as 30%, and epinephrine boluses are usually required to prevent cardiovascular collapse (Aggarwal et al., 1987). Immediately after reperfusion, LV function may be impaired, and PCWP, CVP, and PAP usually increase with a major decrease in SVR, and transesophageal echocardiogram (TEE) monitoring shows a stable or even decreased LV end-diastolic volume. These contradictory findings may be result from a period of deteriorated LV compliance, or cardioplegia, on reperfusion (Suriani et al., 1996; De Wolf, 1999). The etiology of PRS remains unclear, but it may be caused by the release of vasoactive mediators from the ischemic liver or decompressed portal circulation, changes in the rate of venous return (volume overload), and perhaps an increase in serum potassium. Possible mediators that are highly suspect include nitric oxide and tumor necrosis factor-α, with demonstrably increased levels after graft reperfusion (Nishimura et al., 1993), and xanthine oxidase, a generator of cytotoxic oxygen radicals, which may produce myocardial dysfunction and cellular damage. Vasoactive drugs for pressor support (norepinephrine, epinephrine, dopamine) may be required, and a balance is reached between a lowered MAP and often a very low SVR permitting increased flow to perfusable organs at a lower perfusion pressure. High filling pressures should be avoided, as they may cause congestion of the donor liver, bleeding from surgical sites, and biventricular dysfunction with pulmonary edema. Therapies for reducing filling pressures include limiting IV infusions, furosemide-induced diuresis, vasodilation (IV nitroglycerine or morphine), nitric oxide, or prostaglandin E₁.

Blood Loss, Coagulation, and Hemostasis

During liver transplantation surgery, the effects of fibrinolysis, thrombocytopenia, decreased coagulation factors, and fibrinogen deficiency on clinical bleeding are not always predictable, and transfusion requirements are variable. Portal hypertension with fragile venous collaterals, adhesions from prior operations, and lack of surgical hemostasis contribute to blood loss. Independent predictors of increased transfusion requirements include the severity of liver disease or Child-Pugh classification (especially for those hospitalized for inpatient support), preoperative PT, history of abdominal operations, preoperative hematocrit, and factor V levels. In addition, portal vein hypoplasia, the use of a reduced-size liver graft, and increased operative time make surgery technically challenging (Ozier et al., 1995; Maurer and Spence, 2004). Usually, the greatest operative blood loss occurs during vascular dissection and the hepatectomy phase (stage II). During this stage, there is a progressive degradation of the coagulation cascade, and a dilutional coagulopathy with a progressive thrombocytopenia. The blood loss can range from 0.5 to 25 times the patient’s blood volume (Borland et al., 1985).

Alterations of coagulation in the pediatric patient during OLT have been studied (Kang et al., 1989). Classic hourly monitoring of the PT, activated PTT (aPTT), and platelet counts demonstrates a progressive prolongation of the PT and PTT, as well as a significant decrease of all clotting factors. On graft reperfusion, there may be profound prolongation of the PTT, usually to greater than 100 seconds. Besides the standard coagulation tests (PT, aPTT, fibrinogen, platelets, and D-dimer), the thromboelastogram (TEG) and Sonoclot (coagulation and platelet function analyzer) are used in the evaluation of coagulation. The TEG is performed using whole blood; it assesses clot formation until an endpoint of clot lysis or retraction is determined. TEG findings have correlated with clinical bleeding and can assist in treating intraoperative hemorrhage by identifying the cause of the bleeding diathesis (factor deficiency, fibrinolysis, heparin effect, thrombocytopenia, or platelet dysfunction) (Zuckerman et al., 1981; Kang, 1986) (Fig. 28-6). Abnormalities of the reaction time (r), the alpha angle (a), or the maximum amplitude (MA) may indicate decreased clotting factors, diminished factor VIII and fibrinogen, or diminished platelet function or number, respectively (Kang et al., 1989). In contrast, a short reaction time is indicative of a hypercoagulable state. This has occasionally been observed in patients who have developed thrombosis after graft reperfusion (Kang, 1995a, 1995b; Gologorsky et al., 2001; Planinsic et al., 2004).

FIGURE 28-6 Thromboelastogram (TEG). A, The normal parameters measured and analyzed for interpretation of the TEG. B, The coagulation alterations noted during OLT. Note the elements of low platelets (and the improvement in the maximum amplitude after administration of platelets), and the development of fibrinolysis, which is treated by ε-aminocaproic acid (EACA) and detected early on the TEG (at the time of graft reperfusion). Also, the diminished alpha angle in stage 3 is treated with administration of cryoprecipitate, with noted improvement of coagulation.

(From Kang Y, Gelman S: Liver transplantation. In Gelman S, editor: Anesthesia and organ transplantation, Philadelphia, 1987, Saunders, pp 139–185.)

Increased fibrinolytic activity is observed in patients with ESLD as a result of increased tissue plasminogen activator activity and reduced synthesis of fibrinolysis inhibitors. Tissue plasminogen activator further increases during the anhepatic stages and peaks immediately after graft reperfusion. Various antifibrinolytic agents have been used to counter this accelerated fibrinolysis (evident immediately on graft reperfusion in up to 80% of patients), but their precise role remains undefined. These include aprotinin, ε-aminocaproic acid (EACA), and tranexamic acid. Aprotinin, a serine protease inhibitor that prevents the lysis of fibrinogen by inhibiting plasmin, kallikrein, and leukocyte elastase, is no longer available. EACA (Kang et al., 1987) and tranexamic acid prevent fibrinolysis by inhibiting plasminogen and plasmin, thus preventing the eventual degradation of fibrin. In addition, a significant heparin effect may be seen immediately on graft reperfusion for up to 30 minutes. This effect is caused by the release of endogenous heparinoids from the liver, as well as residual heparin from the preservation solution. Calcium is an important coenzyme in the coagulation cascade. During the dissection and anhepatic phases of liver transplantation, hypocalcemia may develop, especially when large amounts of fresh frozen plasma have been given. In many transplantation centers, continuous calcium infusions and magnesium supplements are routine therapy.

The approach to blood product replacement in children differs from that in adults because of two important concerns: thrombosis of the hepatic artery and postoperative hypercoagulability. Thrombosis of the hepatic artery is the most common serious complication after liver transplantation in children, so less fresh frozen plasma and platelets are routinely administered. After reperfusion, the hematocrit should ideally be maintained at 20% to 30% to minimize the increase in blood viscosity and to limit the risk for thrombotic complications (Tisone et al., 1988). Children may be at greater risk for hepatic artery thrombosis than adults because their arteries are smaller, and because of their postoperative hypercoagulable state (Heffron et al., 2003). The incidence of hepatic artery thrombosis has been reported in 15% of the mixed-age; pediatric series (Otte et al., 1990); however, it appears to be directly related to the size of the hepatic artery (smaller arteries and livers from neonates or infants having a higher incidence of this complication) (Mazzaferro et al., 1989; Jurim et al., 1995; Mas et al., 2003; Martin et al., 2004) and to technical complications during the vascular reconstruction. When a split liver is used, thrombosis is relatively rare (5% to 8%) and is similar to the adult rate (Gridelli et al., 2003). Thus, in some institutions, aggressive correction of coagulation is pursued only when there is diffuse bleeding after graft reperfusion or if monitoring reveals fibrinolysis that was not reversed by the new liver. Many transplantation centers use normalization of the PT and platelet count as indicators of recovery of donor liver graft function. Persistent hypothermia, coagulopathy with bleeding, increased serum lactate, hypocapnia, hyperkalemia, acidosis, absence of bile production, hyperglycemia, renal insufficiency, and hemodynamic instability may suggest suboptimal graft function.

After liver transplantation in children, levels of protein C and antithrombin III decrease to below 50% of normal and stay there for 10 days. These prolonged decreases are not seen in adults. Immediately after surgery, a 10-fold increase in plasminogen activator inhibitor occurs, with a further increase 6 to 9 days later. Therefore, in the immediate postoperative period, between days 4 and 10, children are at increased risk for thrombosis (Harper et al., 1988). To minimize this, anticoagulation therapy has been administered (IV heparin, dextran 40, aspirin, and antithrombin III) (Abengochea et al., 1995). There are also differences in coagulation between the infant and adult. In the normal neonate, there is a deficiency of vitamin K–dependent clotting factors (II, VII, IX, X) for several weeks. Protein C is significantly reduced for at least 6 months (Andrew et al., 1987), and protein S concentrations do not increase to within the normal adult range until 3 months of age (Donaldson et al., 1991). Protein C inhibits the function of factors VIII and V and enhances fibrinolysis, which is enhanced by protein S.

When the child’s body weight is greater than 20 kg, use of the rapid infusion system facilitates the rapid replacement of blood products. In this instance, however, blood product replacement is similar to that for an adult. A unit each of RBCs and fresh frozen plasma, and 250 mL of either normal saline solution or neutral pH balanced salt solution (Plasmalyte) is mixed in the cardiotomy reservoir of the rapid infusion system. This mixture mimics whole blood with a hematocrit of 28% to 30%. Blood replacement may occur at a rate of up to 1500 mL/min if needed.

Hypothermia and hypocalcemia are known to contribute to coagulopathy (Kang, 1995a), and they affect platelet function and increase the incidence of fibrinolysis. Thus, temperatures below 35° C are best avoided. Finally, cell salvage may be beneficial in the patient undergoing OLT. Blood recovery of up to 30% is expected, but the need for rapid volume replacement limits its use. In addition, the use of the cell saver is contraindicated in patients with viral or bacterial infections, tumors, or FHF without an identifiable cause of the liver failure. Massive blood transfusion has an associated morbidity of more frequent bouts of sepsis, a prolonged stay in the intensive care unit (ICU), a higher rate of severe CMV infection, and higher rates of graft failure and patient mortality (Maurer and Spence, 2004).

Metabolic Function

Hepatic failure can result in impairment of numerous complex metabolic functions that may significantly impact anesthesia care. The liver plays a critical role in maintaining a normal blood glucose level; hypoglycemia frequently results from failure of gluconeogenesis, insufficient insulin degradation, and a depletion of glycogen stores. Most patients with chronic liver disease are undernourished, and fat stores are diminished with impairment of lipid transport and the integrity of cellular membranes.

Altered Glucose Metabolism

Hypoglycemia is rarely seen except in patients who present with acute FHF or have exhausted their liver glycogen stores. Patients may also be at risk during catecholamine infusions or if they require insulin for the management of hyperkalemia. During the anhepatic phase, several sources of glucose are available to the patient, such as packed RBCs (which contain a significant amount of free glucose: 84 mg/dL by day 35 of storage) (Miller, 2000), 5% dextrose in water (D₅W, used as a carrier for drug infusions), and IV methylprednisolone (used for induction of immunosuppression during the portal anastomosis). Hyperglycemia after graft reperfusion is common because of glucose release from ischemic hepatocytes, steroid-induced insulin resistance, and decreased glucose metabolism in hypothermic patients (DeWolf et al., 1987). Thus, hourly monitoring of blood glucose levels is essential (Fig. 28-7).

FIGURE 28-7 Glucose levels during liver transplantation, as plotted against time. Mean and standard deviation (SD) values are shown. Shaded area represents the anhepatic phase.

(From Borland LM, Roule M, Cook DR: Anesthesia for pediatric orthotopic liver transplantation, Anesth Analg 64:117, 1985.)

Acute Ionized Hypocalcemia and Hypomagnesemia

Ionized hypocalcemia results from the rapid transfusion of large volumes of blood products containing citrate, especially during periods of hypothermia and acidosis. Citrate chelates calcium and magnesium and other divalent cations. Hypotension is the usual consequence and becomes significant at an ionized calcium level of 0.56 mmol/L, at which point the patient may develop cardiovascular collapse (Marquez et al., 1986; Martin et al., 1990).

The consequence of acute ionized hypomagnesemia (Scott et al., 1996) is not yet apparent, but it may result in a higher incidence of atrial arrhythmias and decreased myocardial contractility (Fig. 28-8).

FIGURE 28-8 Changes in magnesium and citrate levels during liver transplantation.

Replacement of calcium is effective with either calcium chloride or gluconate in equivalent calcium dosages. Administration of calcium chloride in the central catheter may result in transient arrhythmia, but deposition into tissues from an extravasated peripheral catheter will result in severe tissue necrosis. The recipient routinely receives sodium bicarbonate and calcium chloride about 1 minute before reperfusion to counteract anticipated hyperkalemia and hypotension.

Hypokalemia

Hypokalemia is the norm in chronic liver failure. It results from the use of diuretics, altered aldosterone metabolism, and metabolic alkalosis. If ventricular arrhythmias are noted during stages I and II, magnesium replacement is recommended. Potassium replacement is avoided because there is an expected transient twofold to threefold increase in potassium concentration immediately on graft reperfusion. Hypokalemia is common after graft reperfusion, usually as a result of diuresis, receptor stimulation with epinephrine, and uptake of potassium by the new liver (Xia et al., 2006). Cautious replacement during the biliary reconstruction phase is appropriate if the patient has no preexisting renal insufficiency and has evidence of adequate urine output.

Hyperkalemia should be treated aggressively at any point during the surgery. This electrolyte disturbance usually results from massive transfusion of RBCs, which have an estimated potassium content of 76 mEq/L by day 35 of cold storage, or from renal failure (Miller, 2000). The judicious use of diuretics as well as an infusion of glucose and insulin may be of benefit in reducing the potassium load (De Wolf et al., 1993). This is most crucial before revascularization of the donor liver. Postreperfusion hyperkalemia (7 to 12 mEq/L) is transitory, with redistribution occurring in 1 to 2 minutes, which seldom needs pharmacologic intervention other than prophylactic sodium bicarbonate and calcium intravenously (Nakasuji and Bookallil, 2000). Washed RBCs prevent the further development of this problem. When hyperkalemia is life threatening, the use of venovenous hemofiltration or removal of part of the patient’s blood volume and washing by the cell saver may be beneficial.

Metabolic acidosis is progressive during OLT and peaks during graft reperfusion. It results from transfusion of blood products and becomes accentuated during the anhepatic stage when liver metabolism of citrate, lactate, and other acids is absent. Whether tissue hypoperfusion is a contributing factor remains unclear; however, this should be balanced by the fact that overall body oxygen consumption is reduced during the anhepatic stage. The threshold for bicarbonate administration is a base deficit (<5 mEq/L). Associated morbidity includes hypernatremia, hypercarbia, and hyperosmolality. Acidosis usually resolves after reperfusion of the graft. Sodium bicarbonate should be administered as indicated and any ongoing problem identified (poor perfusion with lactic acidosis, or delayed primary function or nonfunction of the graft). Metabolic alkalosis is common postoperatively as a result of diuretic therapy and metabolism of citrate or lactate. This may delay weaning of the patient from mechanical ventilation, but it is another useful marker of resumption of hepatocellular function.

Hyponatremia and Hyperosmolarity

Dilutional hyponatremia is common and worrisome at serum sodium levels less than 125 mEq/L. Central pontine myelinolysis (CPM) is a frequently symmetric, noninflammatory demyelinating disorder in the brainstem pons. In at least 10% of patients, demyelination also occurs in extrapontine areas. Clinical manifestations are postoperative confusion or weakness, or a “locked-in” syndrome, after transplantation (Estol et al., 1989; Wszolek et al., 1989). The most frequent findings are delirium, pseudobulbar palsy, and spastic quadriplegia, which may result in permanent neurologic deficits. CPM occurs inconsistently as a complication of severe and prolonged hyponatremia, particularly when the sodium is corrected too rapidly. A study by Singh and coworkers (1994) demonstrated that CPM was present in 29% of postmortem examinations of adults after liver transplantation. Risk factors included serum sodium less than 120 mEq/L for more than 48 hours, aggressive IV fluid therapy with hypertonic saline solutions, and hypernatremia during treatment.

Empirical data show that CPM is likely to occur when the total perioperative increase in sodium concentration is above 15 to 20 mEq/L (Estol et al., 1989; Yu et al., 2004). In these patients, the choice of crystalloid solution should be Plasmalyte or 0.45% NaCl. Hyperosmolality has also been considered a contributor to the development of CPM. In the presence of either of these metabolic derangements, the judicious use of tris(hydroxymethyl)aminomethane (THAM) is recommended because its osmolality is 308 mOsm/L, whereas that of sodium bicarbonate is 2000 mOsm/L. In addition, the sodium content of bicarbonate buffer is 8.4% compared with 0.9% NaCl in IV solutions.

Temperature Regulation

Surgical procedures that place these patients at risk for unintentional hypothermia involve exposure of large skin, serosal, and mucosal surfaces during lengthy procedures under general anesthesia in a cold operating room, especially with no humidification of gases and with infusion of cold IV fluids. The most significant contributors to hypothermia in the pediatric patient undergoing OLT are radiant and evaporative heat losses. In addition, the use of VVB may result in a temperature loss of 0.5° to 1.0° C when a heat exchanger is not used. Preservation of the donor liver depends on rendering the organ metabolically inert by reducing the core temperature to 4° C with cold preservation techniques. To further extend this cooling period while performing the vascular anastomosis in the recipient, the liver may be wrapped in cold compresses or ice, which will further reduce the core temperature of the patient. With reperfusion, a hypothermia-induced cardiac arrhythmia and arrest may result if the perfusate of the liver is allowed to further cool the sinus node. Modest hypothermia (to 35° C) is well tolerated with minimal effects on coagulation, but platelet dysfunction, fibrinolysis, and bleeding begin to increase in a linear fashion as the core temperature decreases. Mild hypothermia may be beneficial, as a reduction in metabolic oxygen requirements may limit warm ischemia and cerebral and myocardial injury. In pediatric patients, the detrimental physiologic effects of mild hypothermia (32° to 35° C) and the increased risk for infection clearly outweigh these minimal benefits.

Attention should be directed to aggressively maintaining a normal body temperature. This may be achieved by using forced-air warming (Bair Hugger) or raising the ambient temperature of the operating theater. In addition, protective barriers should be strategically placed to prevent the operating room table from becoming wet, because this will result in conductive cooling of the patient. Heating of the humidified gases is also an important maneuver. In some cases, intraperitoneal lavage with warmed irrigation after the completion of the arterial anastomosis can be undertaken to assist in warming. Concerns about hypothermia should be communicated with the surgical team, as hypothermia-induced coagulopathy can result in unnecessary nonsurgical hemorrhage, and time spent in warming maneuvers could result in reduced blood loss and improved hemostasis. In the patient receiving Compath, however, hyperthermia is the norm. In this instance, care should be taken to avoid temperatures of 38° C or higher, as this may serve to augment ischemic reperfusion injury of the graft.

Pulmonary Function

Hypoxemia is common in pediatric patients with ESLD because ascites and pleural effusions cause a decrease in FRC and total lung capacity, impaired diffusion capacity, and pulmonary arteriovenous shunting. After the induction of anesthesia, difficulties in ventilation and oxygenation may occur, and diaphragmatic paralysis can result in an acute restrictive lung effect. The increased alveolar-arterial oxygen gradient usually improves after the abdominal cavity is opened. If relative hypoxemia persists, other causes of venous admixture should be sought.

Factors that may worsen oxygenation during the surgical procedure include clot or air emboli, progression of ARDS, transfusion-related acute lung injury, HPS, and pulmonary edema from excessive fluid administration. Finally, extubation of the patient at the end of the procedure is not recommended, no matter how short the duration of the surgery, because 50% to 55% (McAlister et al., 1993) of patients develop right diaphragmatic paralysis postoperatively and 25% will have pleural effusions, which compromise pulmonary function. The fast-track approach to anesthesia care may reduce the requirement for postoperative mechanical ventilation, but it does not reduce the length of stay in the ICU after liver transplantation (Findlay et al., 2002).

Renal Function

Renal insufficiency, a common finding in patients undergoing OLT, contributes significantly to postoperative morbidity, and it is an independent predictor of postoperative mortality (Gonwa, 2005). The patient who comes to the operating room with hepatorenal syndrome or ATN should not be expected to show improvement of renal function until after the graft functions (McCauley et al., 1990). Information collected by the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database support the conclusion that renal insufficiency in patients with FHF and in those requiring preoperative dialysis or liver-kidney transplantation for cirrhosis predicts lower posttransplantation patient and graft survival rates (Brown et al., 1996).

A progressive decline in urine output is expected, with little or none during the anhepatic portion of the surgery without preservation of the IVC or use of VVB. This physiologic alteration has been thought to be secondary to congestion of the kidneys from increased renal venous pressures with total cross-clamping of the infrahepatic IVC (Gunning et al., 1991). Whether the incidence of postoperative renal insufficiency is as frequent when the piggy-back technique is used remains unclear. Thus, the judicious use of the diuretics (mannitol and furosemide) is recommended in the patient who develops oliguria (Polson et al., 1987). It should be noted that furosemide may be ineffective in the patient with a low albumin level (average albumin in the patient with liver failure for OLT is 2.5 to 1.8 mg/dL). Although a renal dosage of dopamine not exceeding 1.5 mcg/kg per min is often recommended, there is no clear benefit from its use as a renal protective agent (Polson et al., 1987; Gray et al., 1991; Swygert et al., 1991; Kellum and Decker, 2001). The incidence of renal complications postoperatively in all patients undergoing OLT remains the same with or without the use of VVB or diuretic therapy (Schwarz et al., 2001; Cabezuelo et al., 2003). Acute renal insufficiency is estimated to occur after liver transplantation in up to 67% of recipients (Rimola et al., 1987). Contributing factors include preexisting renal insufficiency, intraoperative complications (suboptimal renal perfusion associated with hypotension, massive transfusion, increased caval pressures), early graft dysfunction, sepsis, and administration of cyclosporine or tacrolimus and other nephrotoxic drugs in the immediate posttransplantation period.

Small Bowel Transplantation

In the patient scheduled for isolated SBT, the anesthesia management is similar to that for other major abdominal surgeries. The patient usually has a central venous catheter, although it is sometimes placed in an unconventional site if the subclavian and internal jugular veins are thrombosed (right atrial, transhepatic, or direct inferior vena caval catheters). These procedures are lengthy and lend themselves to significant third-space losses and major fluid shifts. Two large-bore IV catheters above the diaphragm and a radial arterial catheter are recommended. CVP should also be monitored as a guide for fluid replacement. If central vein cannulation is impossible, it is best to proceed without its use; femoral vein cannulation can be used for volume replacement. All blood products should be CMV negative and irradiated, to minimize the risk for graft-versus-host disease.

The choice of anesthesia agent depends on the patient’s underlying disease and hemodynamic status. Nitrous oxide should be avoided because it may cause additional bowel distention. The choice of fluids remains controversial in patients undergoing bowel surgery. Not infrequently, significant bowel swelling and distention are noted after reperfusion of the graft. Frequently, diuresis is recommended as a means to treat this problem, although it is often ineffective. Moreover, the etiology of the intestinal edema is most likely related to the preservation of the organ. The use of colloids, preferentially albumin, is recommended when the patient had a low albumin level preoperatively,

Reperfusion of the isolated small bowel graft usually has minimal hemodynamic effects. The reperfusion syndrome seen with liver transplantation is absent because of the relatively low potassium load and the low volume of effluent extruded from the graft. Hemodynamic stability is the norm, and coagulopathy or metabolic derangements are unusual.

Multivisceral Transplantation

Anesthesia considerations for the patient scheduled for multivisceral transplantation are identical to those for the patient undergoing OLT. There are, however, unique and specific considerations with respect to planned vascular anastomoses (Starzl et al., 1993; Todo et al., 1995) (see Fig. 28-16). The liver is usually placed in piggy-back fashion in this instance. A partial cross-clamping of the abdominal aorta should be anticipated for the placement of the arterial anastomosis using a Carrel patch (see Fig. 28-17). The surgical procedure is divided into three stages, similar to those with solitary liver transplantation. Completion of the abdominal viscera exenteration during the preanhepatic stage is the period of greatest blood loss (De Wolf, 1991). Hemodynamic alterations during this period are related to complications of massive transfusion and manipulation of the abdominal viscera. Ionized hypocalcemia, lactic acidosis, and progressive hypothermia should be anticipated. In addition, a progressive coagulopathy, as seen in patients undergoing OLT, is expected. Thus, monitoring of coagulation is essential. The anhepatic stage of the surgery is usually performed without the use of VVB. The liver is placed in piggy-back fashion, and vascular anastomosis of the intestine follows. A significant difference with respect to reperfusion of the multivisceral graft from that of the liver is that the arterial anastomoses must be performed before graft reperfusion. The graft is flushed with 50 mL/kg of cold saline or lactated Ringer’s solution before reperfusion, to reduce the potassium load from the preservation solution.

Reperfusion of the multivisceral graft is similar to that of the hepatic graft. Hypotension and bradycardia are the usual observations secondary to the release of a large volume of hypothermic, hyperkalemic, acidotic preservation solution into the right heart. These changes are usually short lived, with normalization of the hemodynamics within minutes after reperfusion. The incidence of the postreperfusion syndrome in this group of patients is not well defined.