Liver transplantation: Perioperative anesthetic considerations

COVID-19 pandemic

The COVID-19 pandemic, named for the illness caused by the SARS-CoV-2 virus, has been spreading across the world since the end of 2019 and has challenged the (liver) transplantation system worldwide, resulting in a temporary decrease of transplant activities.

This epidemic presents multiple issues for liver transplant centers: (1) the straining of resources (limited intensive care unit [ICU] bed and equipment availability); (2) the concerns for the risk of nosocomial COVID-19 infection in recipients, and the possibility of transmitting the disease to healthcare workers; and (3) the recognition that COVID-19 may manifest with hepatic signs and symptoms common to other forms of acute hepatitis, mandating that patients presenting with newly elevated serum liver enzymes undergo a comprehensive differential diagnostic process. The orthotopic liver transplantation (OLT) community has responded to these challenges by creating “COVID-19 protocols,” which often include screening for both donors and recipients before liver transplant ; the use of “good-quality graft,” which will likely result in expeditious recipient recovery and discharge from hospitals ; and the use of telemedicine to minimize the need for bringing in OLT candidates for transplant evaluation and recipients for routine follow-up visits.

It is too soon to draw any conclusions on the effectiveness of these measures to support clinical activities and protect patients and healthcare team members. Liver transplant centers should therefore continue to use caution and closely monitor their performance and clinical outcomes.

Central nervous system

Hepatic encephalopathy (HE) is a progressive but potentially reversible syndrome of the central nervous system (CNS) associated with variable degrees of brain edema. Presentation ranges from subclinical to coma. HE is an overt or covert manifestation of cirrhosis in up to 80% of cirrhotic patients, and it is a defining sign and main cause of death in acute liver failure (ALF) ^, (see Chapters 77 , 78 , and 105 ). Based on the etiology, the American Association for the Study of Liver Diseases (AASLD) recognizes that type A is associated with ALF, type B with a transjugular intrahepatic portosystemic shunt (TIPS), and type C with cirrhosis. Based on the severity of neurologic impairment, HE ranges from unimpaired to minimal (grade 0) to coma and brain death (grade 4). Because presence and severity of HE is of prognostic significance, including impaired brain recovery post-transplant, experts have called for its inclusion into the MELD score (see Chapter 4 ).

The pathophysiology of HE is complex and incompletely understood. Evidence supports the central role of ammonia, which bypasses first-pass liver clearance via portosystemic shunting. Ammonia crosses the blood–brain barrier (BBB) and promotes astrocyte and neuronal swelling by increasing intracellular glutamine content and creating osmotic imbalance. Transported to the mitochondria, glutamine contributes to production of reactive oxygen species (ROS) and activation of mitochondrial transition permeability pore and various kinases, resulting in cytotoxic swelling. Increased ammonia levels have been shown to alter cerebral blood flow and brain glucose utilization. ^, High arterial and brain levels of ammonia in ALF correlate well with cerebral edema and increased intracranial pressure (ICP), with consequent high risk of mortality from brain herniation and hypoxia.

Multiple other endogenous mediators have been implicated, including benzodiazepine- or γ-aminobutyric acid (GABA)–like agonists and neurosteroids acting on GABA _A receptors, ROS, inflammatory cytokines, hyponatremia, and manganese. Other evidence implicates neuroinflammation, including activation of microglia and proinflammatory cytokines and as a cause of altered permeability of the BBB leading to vasogenic edema and accumulation of ammonia in the brain. ^{, ,} Low-grade brain edema, evident on advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging, is associated with increased interstitial water caused by BBB breakdown and seems to be more common in chronic liver disease (CLD) than initially appreciated. ICP remains mostly normal in part because of the neuronal loss.

In cirrhosis, HE has a slow onset, a progressive course, and only partial responsiveness to therapy. Significant cerebral edema typically does not develop, and a precipitating event (e.g., infection, excessive dietary protein, dehydration, gastrointestinal [GI] bleeding) can be often identified. TIPS, a known risk factor, is associated with 30% of new or worsening encephalopathy. In addition to correction of any precipitating factors, treatment includes nonabsorbable disaccharides, which reduce the intestinal production and absorption of ammonia; antibiotics that target urease-producing bacteria; ornithine and acarbose; benzodiazepine receptor antagonists; and probiotics. Minocycline, an agent with potent central anti-inflammatory properties, reduces neuroinflammation, brain edema, and encephalopathy in liver failure, as does the anti–tumor necrosis factor (TNF) agent etanercept. The molecular absorbent recirculating system (MARS) and therapeutic plasma exchange (TPE) improve hemodynamics and grade of HE in ALF and acute-on-chronic liver failure, with TPE also improving survival in ALF, but more studies need to be done.

The hallmarks of HE in ALF are cerebral edema and increased ICP. Both are life-threatening complications of grade 3 and 4 encephalopathy. Treatment includes several general and specific interventions aimed at promoting cerebral perfusion pressure (CPP) above 60 mm Hg ( Table 106.1 ); this is achieved by maintaining the mean arterial pressure (MAP) and reducing ICP to below 20 mm Hg by reducing brain edema. Grade 3 or 4 HE requires endotracheal intubation for airway protection. Mild hyperventilation temporarily relieves brain hyperemia, but prolonged hyperventilation is not beneficial and may cause CNS ischemia. Mannitol is effective in reducing ICP in the short term, but prophylactic use is not recommended. N-acetylcysteine treatment may also prolong transplant-free survival in ALF unrelated to paracetamol/acetaminophen toxicity. ^,

The role of ICP monitoring is controversial because it is associated with a high risk of bleeding in this patient population and little data exist to support its role in improving patient outcomes. ICP monitoring has been recommended in ALF and comatose patients with computed tomography (CT) evidence of brain edema. A noninvasive alternative to ICP monitors is transcranial Doppler (TCD) sonography. By measuring blood flow velocities in middle and anterior cerebral arteries and calculating resistance and pulsatility indexes, TCD allows serial estimates of cerebral blood flow in the setting of impaired autoregulation and developing brain edema. In a small series of ALF patients, the feasibility of intraoperative TCD to assess main cerebrovascular hemodynamic parameters was recently demonstrated, but more studies are needed to ascertain the value of intraoperative TCD in OLT.

Mild to moderate hypothermia (32°C–35°C) reduces brain ammonia and cytokine levels and in part restores cerebrovascular autoregulation and brain glucose metabolism. Although experimental evidence provides a strong rationale, only limited clinical data on efficacy and safety of hypothermia in humans with ALF are available, and future studies are warranted. ^{, ,}

Cardiovascular system

Cardiovascular complications are responsible for the majority of nongraft morbidity and mortality in the early post-OLT period (see Chapter 111 ). Common clinical problems that impact postoperative outcomes include hyperdynamic circulation, CAD, and nonischemic cirrhotic cardiomyopathy.

Pulmonary system

As many as 70% of patients with CLD have respiratory problems, which manifest as impaired respiratory mechanics and gas exchange. Most pulmonary comorbidities are independent from liver disease, but for a few exceptions such as α ₁ -antitrypsin deficiency and cystic fibrosis. Pulmonary evaluation includes history and physical examination, radiologic studies, arterial blood gases (ABGs), and pulmonary function tests. Right-sided heart catheterization is indicated when clinical or echocardiographic evidence suggests significant pulmonary hypertension.

Hemostasis in end-stage liver disease

The traditional view that ESLD is a hypocoagulable state has been revised (see Chapters 77 and 78 ). The current concept emphasizes complex disturbances of procoagulant, anticoagulant, and fibrinolytic pathways and platelet function, that result in rebalancing of the hemostatic system. ^, The resulting fragile, rebalanced state can be easily tipped towards hypocoagulability and bleeding or towards hypercoagulability and thromboembolism. Importantly, the latter is still an often-underestimated risk in ESLD.

Understanding the hemostatic system in ESLD is essential to perioperative coagulation management and optimization of blood-product transfusion practices, which are related to morbidity and mortality in LT. ^, Deficiency in primary hemostasis is caused by quantitative and qualitative platelet changes. Mild to moderate thrombocytopenia is common. Causes are splenomegalic platelet sequestration in portal hypertension, impaired megakaryocytopoiesis from reduced production of thrombopoietin by the cirrhotic liver, folic acid deficiency in alcoholic cirrhosis or acute hepatitis C infection, and reduced platelet half-life related to autoantibodies. Evidence for impaired platelet aggregation and adhesion in cirrhosis is controversial. The proposed mechanisms are complex and multifactorial, including the role of two potent endothelium-derived platelet inhibitors, nitric oxide, and prostacyclin. More recent work suggests that the functional capacity of platelets in cirrhosis may be preserved, suggesting that the main defect in primary hemostasis is thrombocytopenia. A compensatory mechanism for the deficient platelet function in cirrhosis is an increase in endothelium-synthesized von Willebrand factor (vWF), because of deficiency in ADAMTS-13, a vWF cleaving protease that is reduced in cirrhosis. The upregulated vWF promotes adhesion of platelets to injured endothelium and may explain the poor correlation between platelet number and bleeding time. Thrombocytopenia, as low as 60 × 10 ⁹ per liter, is sufficient to preserve thrombin generation at a level equivalent to the lower limit of normal.

The liver synthesizes all procoagulant factors except for vWF, which is synthesized by the endothelium. Factor VIII is synthesized by hepatocytes but also by nonhepatic sinusoidal endothelial cells. Reduced levels of coagulation factors are observed in acute and chronic liver disease. Several factors—II, VII, IX, and X—are vitamin K-dependent and exist in plasma as inactive precursors when vitamin K is deficient in decreased absorption (cholestasis) or antagonism (warfarin). In ALF, plasma concentrations of coagulation factors with the shortest half-life (factor VII, 4–6 hours; factor V, 12 hours) decrease first, followed by those with a longer half-life. Exceptions are factors VIII and vWF, which may be elevated in chronic and acute liver disease because of inflammatory cytokine-mediated upregulated extrahepatic production. Fibrinogen is usually well preserved: its decrease is a mark of advanced cirrhosis or ALF. Even when levels are normal, fibrinogen is often functionally aberrant because of impaired fibrin polymerization. The result is an abnormal thrombin time (TT), despite normal international normalized ratio (INR) and partial thromboplastin time (PTT).

The deficiency in procoagulant factors is, at least in part, offset by decreased production of anticoagulants, including proteins C and S, antithrombin, and heparin cofactor II. Proteins C and S are vitamin K dependent and may be deficient in cholestatic disease, and although genetic deficiency of these two proteins is rare, such deficiency is found in both Budd-Chiari syndrome and portal vein (PV) thrombosis. Antithrombin is synthesized by hepatocytes and endothelium, deficiencies are usually mild, and thromboembolic complications are rare.

All proteins involved in fibrinolysis are synthesized by the liver except tissue plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1). Consequently, reduced levels of liver-synthesized factors—plasminogen, plasmin inhibitor, thrombin activatable fibrinolysis inhibitor (TAFI), and factor XIII—are found in both ALF and chronic liver failure. Cirrhosis is classically associated with hyperfibrinolysis, whereas patients in ALF may have hypofibrinolysis because of increased production of PAI-1. The expert viewpoint emphasizes that balance of profibrinolytic and antifibrinolytic factors in liver disease is often restored, and the role of hyperfibrinolysis in bleeding is limited. Increased levels of fibrinogen degradation indicators—d-dimers, plasmin-antiplasmin and thrombin-antithrombin complexes, thrombin fragment F1+2—could be explained by delayed clearance by the diseased liver. Coagulation tests, such as prothrombin time (PT) and activated PTT (aPTT) are used to assess the severity of synthetic dysfunction, and PT-INR is a part of the Child-Turcotte-Pugh (CTP) and MELD prognostic indexes. As tests of in vivo coagulation function, PT-INR and PTT are conceptually deficient because they measure only the procoagulant pathway and ignore the anticoagulant function. The seminal observation that thrombin generation in cirrhotic patients is close to normal may, in part, explain why PT-INR and PTT are poor predictors of bleeding in cirrhosis and liver transplantation. ^, Viscoelastic tests, thromboelastography (TEG, Haemonetics Corporation, Braintree, MA) and rotation thromboelastometry (ROTEM; Pentapharm, Munich, Germany) have the advantage of assaying whole-blood clot formation and lysis, including the platelet contribution, but do not incorporate the endothelial component (see Intraoperative Monitoring, later). Importantly, these assays allow for easy recognition of hypercoagulable states ( Fig. 106.1 ).

Renal system

Renal failure confers increased risk of death to cirrhotic patients, both while on the waiting list and after LT. Even mild renal disease increases the risk of cardiovascular and all-cause mortality. Implementation of the MELD score in 2002 has prioritized patients with renal failure waiting for a liver transplant, resulting in reduced overall mortality on the transplant list. Hepatorenal syndrome (HRS) is a specific type of functional renal failure in patients with decompensated cirrhosis (see Chapters 77 and 78 ). It is marked by renal vasoconstriction and a severe reduction in glomerular filtration rate (GFR < 30 mL/min) but only minimal histologic abnormalities. ^, The primary pathophysiologic process is a circulatory disturbance: portal hypertension facilitates translocation of bacteria from the intestinal lumen into the mesenteric lymph nodes and induces production of inflammatory cytokines and local vasodilators, such as nitric oxide, carbon monoxide, and endogenous cannabinoids. Resulting splanchnic vasodilation decreases the overall SVR and activates several compensatory mechanisms. The initial response is hyperdynamic and includes tachycardia, increased cardiac output, low SVR, and hypotension. With progression of cirrhosis, sympathetic and renin-angiotensin vasoconstrictor systems are activated and temporarily maintain arterial blood pressure (BP), but they also cause renal vasoconstriction and hypoperfusion. Activation of nonosmotic hypersecretion of arginine vasopressin, aimed at preserving circulatory volume, results in retention of solute-free water with attendant hyponatremia, edema, and ascites. HRS is almost invariably associated with ascites and rarely develops in its absence. Onset of HRS is often triggered by a discrete event, such as spontaneous bacterial peritonitis, use of nonsteroidal antiinflammatory drugs (NSAIDs), or hypovolemia because of diuretic use, GI bleeding, or fluid losses. Recently, inflammation has emerged as an important determinant in the development of HRS. Until recently, serum creatinine (SCr) values above 1.5 mg/dL (133 μmol/L) were used to define renal insufficiency in cirrhosis. ^, In 2012 the definition of acute renal failure (ARF) was updated and replaced by acute kidney injury (AKI). AKI is a syndrome with multiple possible etiologies. In 2015 a revised definition of AKI in cirrhosis was proposed, with a new “dynamic” scoring system called International Club of Ascites (ICA)-AKI ; AKI is diagnosed by an increase in absolute SCr of more than 0.3 mg/dL or by a 1.5- to 2-fold increase from baseline. Three categories of increasing severity are defined by levels of SCr or initiation of renal replacement. In the presence of AKI, it is important to differentiate acute tubular necrosis (ATN) from the “classical” hepatorenal syndrome because the therapeutic approach is different, even if the two entities are currently considered a continuum. Vasoconstrictors (such as terlipressin) are not indicated for the treatment of ATN.

Measurement of SCr remains the primary test of renal function despite its well-known limitations. GFR and creatinine clearance are more accurate but less practical tests when repeated assessments are needed. Other tests measure serum and urinary electrolytes, fractional sodium excretion (FeNa), albumin, osmolarity, sediment, and biologic markers. No specific diagnostic test exists for HRS. Rather, diagnosis is based on the presence of liver disease, a precipitating factor, and FeNa less than 1%, signifying preserved tubular reabsorption; however, the latter test is invalidated in the presence of diuretics. Still, recent investigations have suggested that several urine biomarkers may have a diagnostic and prognostic value in cirrhotic patients with AKI. Neutrophil gelatinase-associated lipocalin (NGAL), interleukin (IL)-18, and albumin appear particularly promising in cirrhotic patients. NGAL and IL-18 are associated with tubular renal injury, whereas albumin is associated with glomerular injury. More specifically, NGAL and IL-18 levels are much higher in patients with ATN than in those with HRS-AKI of prerenal, hypovolemia-induced AKI.

General treatment measures are aimed at preventing infection, in particular subacute bacterial peritonitis; maintaining adequate intravascular volume; and avoiding nephrotoxic agents. Circulatory volume losses, often the result of large-volume paracentesis or a GI bleed, are best treated with albumin or, if indicated, by blood products and not with crystalloids, to avoid retention of solute-free water. The main pharmacologic approach uses vasoconstrictors, including a selective vasopressin V1 receptor agonist (e.g., terlipressin) or α-adrenergic agonists (e.g., norepinephrine, midodrine). Vasoconstrictors in conjunction with albumin are only modestly beneficial but are the best medical therapy currently available. Placement of a TIPS improves renal function and GFR and reduces sympathetic and renin-angiotensin-aldosterone axis activation in about 60% of patients. No advantage in survival has been demonstrated in patients with refractory ascites treated by TIPS compared with repeated paracentesis and intravascular volume replacement with albumin. Renal replacement therapy (RRT) offers a bridge to transplant, but the optimal RRT method in HRS and the benefit to patient outcomes are not known. ^, Continuous venovenous hemodialysis (CVVHD) seems to be hemodynamically the most favorable form of RRT. ^, CVVHD can be used to effectively control intravascular volume, pH levels, and solutes (Na, K, SCr, urea, ammonia). In addition, it corrects sodium in a time-controlled fashion, which is particularly relevant to minimize the risk of CNS demyelination in patients with hyponatremia. LT is the treatment of choice for patients with cirrhosis and HRS. About 90% of patients with HRS recover kidney function after successful LT. The remaining 10% do not recover their kidney function and require prolonged RRT and eventual kidney transplantation. Listing criteria for simultaneous liver and kidney transplant, based on OPTN guidelines, include factors such as duration of AKI and RRT and evidence of CKD.

Enhanced recovery protocols

Enhanced recovery after surgery (ERAS), first published in colorectal surgery, pertains to a highly coordinated, multidisciplinary surgical patient care continuum, driven by evidence-based protocols and best practices (see Chapter 27 ). The continuum spans from preoperative medical and nutritional optimization, prehabilitation to offset frailty, and standardization of intraoperative surgical and anesthetic care to postoperative care, including analgesia, early removal of drains and tubes, early mobilization, and rehabilitation. Benefits of ERAS pathways are well documented in several surgical specialties and include improved outcomes and patient satisfaction and reduced LOS and cost. Most transplant centers have well-developed protocols that incorporate individual ERAS elements (e.g., the use of regional techniques for analgesia), but published evidence of a comprehensive ERAS program in LT is limited. ^, A small single-center randomized controlled trial (RCT) demonstrated decreased blood loss and transfusion requirements and another small pilot study demonstrated a decrease in ICU and hospital stay with no other outcome differences. It is increasingly recognized that the concept of ERAS has been applied safely and effectively across surgical subspecialties and that it should be adopted in OLT through center-specific standardization of care.