Hepatic Syndromes

The hemodynamic changes in chronic liver disease contribute to the spectrum of cardiopulmonary disease associated with cirrhosis and portal hypertension. The hyperdynamic state with high cardiac output, portal hypertension with the development of collateral flows, together with an imbalance of vasoactive mediators, leads to characteristic changes in both flow and pressure through the pulmonary vasculature. This may be associated with hypoxia and orthodeoxia. Two ends of the spectrum are hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH). The two conditions are uncommon but important because they have vastly different impacts on risk and long-term outcome. The relative shift of blood from the arterial compartment to the portal system predisposes to a type of prerenal kidney failure, hepatorenal syndrome (HRS).

Cardiac Disease

Cardiac disease may result from chronic liver disease or a primary cardiac disorder. Certain liver diseases are associated with cardiac malformations such as Alagille syndrome (pulmonary stenosis) or biliary atresia with splenic malformation (absent inferior vena cava [IVC], septal defects, and anomalous pulmonary venous drainage). Additionally, small interatrial/ventricular connections may be picked up incidentally on echocardiography. Chronic liver disease results in reduced systemic vascular resistance and an elevated cardiac output, as well as causing cardiomyopathy in some children. Certain diseases, such as hemochromatosis or primary hyperoxaluria, result in deposition of iron or crystals within the myocardium, resulting in impaired function and conduction defects. Anthracycline chemotherapy for hepatoblastoma may cause dilated cardiomyopathy or endomyocardial fibrosis. Finally, pulmonary hypertension may be present either because of PPH or secondary to chronic lung disease such as cystic fibrosis (CF).

Fitness for liver transplantation requires functional assessment to predict whether the myocardium will tolerate caval clamping (particularly in noncirrhotic children) and the profound hemodynamic insult during reperfusion. In most cases, an echocardiogram will define myocardial competence. Where stenoses occur, such as in Alagille syndrome, a measure of the gradient across the stenosis and requirement for dilatation/stenting must be ascertained. In the presence of right ventricular hypertension, pressures should be measured by right heart catheterization at rest and with dobutamine stress. Generally, right heart pressures less than 40% of systemic when stressed will be acceptable for transplantation, providing the cardiac output can be augmented by circa 40% with dobutamine.

Most cirrhotic children with pulmonary hypertension and normal cardiac anatomy are likely to have normal pulmonary vascular resistance (PVR), with hypertension resulting from increased flow through the pulmonary vasculature. These patients have a good prognosis post-transplantation. A small subset will have raised PVR and a hyperdynamic flow state (PPH), which confers increased mortality. In children, the pulmonary pressure needs to be correlated with the systemic pressures and treated if above 50% systemic until the PVR returns toward normal. Intravenous prostacyclin remains the treatment of choice in the acute or severe inpatient setting. Resolution is not guaranteed with transplantation, and progression can be a feature. Perioperatively, the higher the mean pulmonary artery pressure, PVR, and transpulmonary gradient, the greater the risk of death from acute right ventricular decompensation.

Interatrial or interventricular connections pose a conundrum. Small intracavity shunts with a normal direction of flow pose few problems in childhood and often spontaneously close. Cardiologists prefer to leave these lesions unoperated until the child is older. This is acceptable for the healthy child or if the liver disease is well controlled; however, should the liver function deteriorate rapidly, then cardiac intervention in a cirrhotic child poses an excessive procedural risk, but the risk of embolization on reperfusion may be prohibitive for transplantation. Therefore a pragmatic approach is required; very small lesions with normal functional echocardiography can be transplanted with caution taken during reperfusion. Large communications with obvious flow reversal on echocardiography require timed cardiological intervention before the onset of severe cirrhosis and consideration for transplant.

Respiratory Disease

Respiratory compromise commonly results from diaphragmatic splinting from tense ascites, but pleural effusions, chest infections, HPS, or pulmonary edema in acute liver failure may all cause hypoxemia. Primary lung disorders include CF and alpha-1 antitrypsin deficiency, although the latter typically causes symptoms only in adulthood.

HPS occurs in patients with cirrhosis and is characterized by arterial hypoxemia secondary to pulmonary vascular dilatations at the pre- and post-capillary levels. In the most severe cases, arteriovenous malformations may be present. The degree of hypoxemia is not correlated to the severity of liver disease, and HPS is an indication for transplantation. Bubble contrast echocardiography is diagnostic for HPS, and if severe, a technetium-99-radiolabeled macroaggregated albumin perfusion scan is performed to quantify the shunt fraction; above 20% is associated with poorer outcomes ( Fig. 15.2 ). Oxygen therapy is the mainstay for the majority on the waiting list. In patients with severe hypoxemia, embolization may be attempted to reduce the right-to-left shunt. Resolution of hypoxemia occurs gradually, with remodeling of the pulmonary vasculature in 85% of patients post-transplant, although these patients have reduced survival.

Technetium-99 radiolabeled macroaggregated albumin perfusion scan. (A) Normal study highlighting no uptake of tracer in the brain or kidneys. (B) Hepatopulmonary syndrome, demonstrating tracer uptake in the brain and kidneys with a total shunt fraction 13%.

Around one-third of patients with CF will develop liver disease, with 5% of CF children requiring liver transplantation; however, assessment of respiratory function (lung function assessment, chest CT) and infection history must be undertaken before listing.

Renal Disease

Renal dysfunction is less common in children with liver disease; however, it may occur secondary to repeated episodes of cholangitis, in primary renal disorders (primary hyperoxaluria and polycystic liver/kidney disease), in multivisceral transplant candidates, or in children awaiting retransplantation (nephrotoxic drugs, graft dysfunction). Some children may require a combined liver-kidney transplant, for example, in primary hyperoxaluria.

Serum creatinine and urea may be unreliable measures of renal function owing to poor muscle mass; therefore, creatinine clearance or cystatin C is measured. Renal dysfunction occurs in one-third of children post-transplantation, and temporary renal filtration is sometimes required to assist immature nephrons in the fluid removal to protect the lungs in neonates and infants.

HRS is a potentially reversible cause of renal dysfunction in approximately 5% of children with cirrhosis. It represents an advanced stage of hemodynamic dysfunction, and the diagnosis is one of exclusion. HRS confers a worse prognosis even with transplantation, which is the only treatment. Normalization of sodium excretion, serum creatinine, and neurohormonal levels occurs within 1 month of transplantation.

Neurological Disease

Some metabolic syndromes are associated with neurodevelopmental delay and liver disease. The delay or arrested progression of neurological disability with liver transplantation has facilitated referrals in many of these syndromes. Some mitochondrial disorders are also associated with neurological impairment, although transplantation may not always impact the progression of disability despite prolonging life expectancy, raising ethical debate regarding organ utilization.

Hepatic encephalopathy is sometimes subtle, especially in young children with neurodevelopmental delays in end-stage liver disease. In acute liver failure, the onset may be far more dramatic and profound, reflecting cerebral edema and mandating full neuroprotective measures. The exact mechanisms are still unknown, although elevated arterial ammonia levels are often used to monitor progression. Hypoglycemia and intercurrent sepsis must be excluded and treated promptly.

Too Sick to Transplant?

There are few absolute anesthetic contraindications to liver transplantation. The key question that needs to be ascertained is whether the child’s physiology can support the vigorous insult of transplant surgery and the stormy reperfusion. Our strategy is to aim for a cardiac system able to increase its cardiac output by approximately 40% and the respiratory system sufficiently robust to enable the child to be weaned from mechanical ventilation.

Multiorgan failure at the time of transplant considerably complicates outcome. This is often encountered in acute liver failure and in the context of acute exacerbations of chronic liver disease. The strategy in this scenario is to persevere with optimizing cardiopulmonary organ function enough to create a window of opportunity for safe transplantation despite the heightened intraoperative risk. Examples where transplantation may be considered too high risk include children not able to be weaned from oscillatory ventilation, a clear trend in rapidly rising oxygen requirements, unstable hemodynamics (maximal inotropes, arrhythmias), and irreversible brainstem dysfunction.

Set up and Equipment

The anesthetic management is focused on the fact that blood loss may be massive and rapid, and coagulopathy and acidosis that develop with hypothermia must be prevented. The impact of reperfusion may be considerable, and electrolyte, glucose, and acid–base status must be controlled.

The blood transfusion service is integral to the theater episode, and cross-matched blood should be available before the patient is collected. Packed red cell, clotting factor, and platelet transfusion are guided by arterial blood gas analysis (ABG), thromboelastography (TEG), and laboratory full blood count and clotting profile, including a fibrinogen assay.

Peripheral venous access is often achieved on the ward preoperatively, enabling intravenous induction with either thiopentone or propofol. Alternatively, inhalational induction with sevoflurane is chosen. Muscle relaxation is achieved with a nondepolarizing drug. A second, larger cannula can be sited after induction. The airway is secured with an oral endotracheal tube. Ventilation is titrated to achieve a tidal volume of 7 mL/kg and to optimize gas exchange, with ventilatory peak pressures often falling once the abdomen is opened.

Care is taken to protect pressure areas. A warming mattress and warmed fluid lines for rapid volume resuscitation are essential. A nasogastric tube for decompressing the stomach is placed with caution to avoid epistaxis, and a urinary catheter is placed for measuring renal output.

Cannulation of the radial artery with a 22-g or 24-g cannula is preferred. Rarely, femoral or axillary arteries may have to be used, although the potential need for aortic cross-clamping for arterial anastomosis in neonates makes this option less favorable. Pulse contour analysis of cardiac output is available in the theater; however, these technologies are yet to be validated in pediatrics.

Central venous access must be achieved above the diaphragm because of complete caval clamping avoiding interruption of drug infusions and fluid boluses. A 5.5- to 7.5-Fr triple lumen catheter is placed under ultrasound guidance, preferably in the internal jugular vein, although subclavian and axillary veins are acceptable.

Anesthesia is maintained with isoflurane in an oxygen air mix. A fentanyl infusion provides analgesia, and atracurium infusion provides muscle relaxation. Infusions of vasopressor or inotropic agents may be required, most commonly norepinephrine. A dextrose 10% infusion is started at the beginning of the procedure, with the rate titrated to hourly analyses. Antibiotic prophylaxis with piperacillin/tazobactam is administered before the surgical incision.

Surgical Stages and Predictable Consequences for the Anesthetist

Factors Influencing Anesthesia

Coagulation in Liver Disease and Fluid Replacement During Transplantation

Traditional laboratory tests (international normalized ratio [INR], activated partial thromboplastin time, platelet count) would convince us that chronic liver disease is associated with coagulopathy. Various studies in chronic liver disease and acute liver failure, however, have challenged the validity of these tests as a predictor of coagulopathy ; instead, the use of thromboelastography (TEG) and rotational thromboelastometry (ROTEM) has enabled anesthetists to monitor functional coagulation derangements in real time, with a targeted correction of abnormalities minimizing the unnecessary use of blood components ( Fig. 15.3 ).

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