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Korean J Transplant 2023; 37(4): 221-228

Published online December 31, 2023

https://doi.org/10.4285/kjt.23.0061

© The Korean Society for Transplantation

An overview of unresolved issues in the perioperative management of liver transplant patients

Saurabh Mittal1 , Medha Bhardwaj2 , Praveenkumar Shekhrajka3 , Vipin Kumar Goyal1 , Ganesh Ramaji Nimje1 , Sakshi Kanoji1 , Suma Katyaeni Danduri1 , Anshul Vishnoi1

1Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
2Department of Neuro-Anaesthesia, Mahatma Gandhi Medical College and Hospital, Jaipur, India
3Department of Anaesthesia, Mahatma Gandhi Medical College and Hospital, Jaipur, India

Correspondence to: Vipin Kumar Goyal
Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Sitapura, Jaipur 302022, India
E-mail: dr.vipin28@gmail.com

Received: October 26, 2023; Revised: November 20, 2023; Accepted: November 21, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Over the past decade, the field of solid organ transplantation has undergone significant changes, with some of the most notable advancements occurring in liver transplantation. Recent years have seen substantial progress in preoperative patient optimization protocols, anesthesia monitoring, coagulation management, and fluid management, among other areas. These improvements have led to excellent perioperative outcomes for all surgical patients, including those undergoing liver transplantation. In the last few decades, there have been numerous publications in the field of liver transplantation, but controversies related to perioperative management of liver transplant recipients persist. In this review article, we address the unresolved issues surrounding the anesthetic management of patients scheduled for liver transplantation.

Keywords: Coronary artery disease, End-stage liver disease, Intracranial pressure, Liver transplantation, Pulmonary hypertension

HIGHLIGHTS
  • In recent years, significant advancements have been made in preoperative patient optimization protocols, anesthesia monitoring, coagulation management, and fluid management.

  • These improvements have led to excellent perioperative outcomes for all surgical patients, including those undergoing liver transplantation.

  • Some unresolved issues still exist regarding perioperative anesthesia in patients during liver transplantation.

Over the past decade, the field of solid organ transplantation has undergone significant changes, with some of the most notable advancements occurring in liver transplantation. Currently, liver transplantation is recognized as the optimal treatment for patients with end-stage liver disease (ESLD) caused by conditions such as alcoholic hepatitis, nonalcoholic steatohepatitis, viral hepatitis, hepatocellular carcinoma, acute fulminant hepatic failure, and hilar cholangiocarcinoma. Recent improvements in perioperative management have led to outstanding survival rates for liver transplant recipients. However, there remain several areas of debate concerning the perioperative anesthesia management of patients during liver transplantation. This review addresses the ongoing unresolved issues surrounding the anesthetic management of individuals scheduled for liver transplantation.

Cardiovascular diseases, such as coronary artery disease, cirrhotic cardiomyopathy, valvular heart disease, and arrhythmias, are commonly identified during the preoperative work-up for liver transplantation. Coronary artery disease is particularly prevalent among patients scheduled for liver transplantation, and its incidence is on the rise. This increase is attributed to the growing acceptance of older recipients and the rising incidence of nonalcoholic steatohepatitis leading to liver failure [1]. Cirrhotic cardiomyopathy is a distinctive sequela of long-standing liver disease defined as systolic dysfunction (ejection fraction ≤50% or global longitudinal strain <18% or >22%) and diastolic dysfunction (≥3 of any of the following: septal e’ velocity <7 cm/s, E/e’ ratio ≥15, left atrial volume index [LAVI] >34 mL/m2, tricuspid regurgitation [TR] velocity >2.8 m/s). Although patients with cirrhotic cardiomyopathy, are asymptomatic at rest, heart failure is quite high in these patients during stress, such as liver transplantation [2]. Even recipients with a normal ejection fraction but high probability score (Heart Failure Association–PEFF diagnostic score 5–6) due to preoperative risk factors such as advanced age, female sex, anemia, hypertension, or dyslipidemia is associated with an increased risk of postoperative heart failure with preserved ejection fraction (HFpEF) and poor long-term survival after liver transplantation [3]. Salah et al. [4] also concluded that nonalcoholic fatty liver disease (NAFLD) is closely associated with the development and progression of HFpEF, and further studies are required for screening, risk stratification, and establishing the impact on clinical outcomes.

Cardiac events, including left ventricular failure, myocardial infarction, fatal arrhythmias, and sudden cardiac arrest, are major contributors to perioperative mortality and morbidity among liver transplant recipients [5]. Therefore, preoperative cardiac evaluation and optimization are essential for patients with ESLD and necessitate the collaborative efforts of cardiologists, anesthesiologists, and hepatologists from the outset. Given these patients' limited physical capacity, noninvasive screening tests such as electrocardiography (ECG), 2-dimensional echocardiography, and cardiac stress testing are routinely performed before transplantation at most centers. However, the efficacy of these cardiac screening tests has been called into question due to their low sensitivity and specificity in ESLD patients and the poor correlation with postoperative cardiac outcomes. QT prolongation, observed in approximately 40%–55% of ESLD patients on ECG, has limited prognostic value. Moreover, several confounders, including hypothyroidism, electrolyte abnormalities, obesity, and certain medications, can also prolong the QT interval [6]. Dobutamine stress echocardiography often yields false-negative results in patients with cirrhosis due to a blunted inotropic response, resulting in a low negative predictive value [7]. An elevated level of postoperative B-type natriuretic peptide (BNP) has been associated with high postoperative mortality. Although increased post-liver transplant BNP is multifactorial, a high preoperative BNP level is closely linked and can help in risk stratification before transplantation [8]. Consequently, the ideal screening tool for cardiovascular assessment prior to liver transplantation remains uncertain. Additionally, the appropriate frequency of cardiac risk assessment for patients on the waiting list is a contentious issue. Recent evidence has begun to support the use of invasive or noninvasive coronary angiography, which has proven to be more accurate in diagnosing coronary artery disease in ESLD patients with minimal or no risk [9,10].

Portopulmonary hypertension is a complication associated with long-standing ESLD. It is characterized by a mean pulmonary artery pressure of 25 mmHg or greater, increased pulmonary vascular resistance exceeding 240 dyne·sec/cm5, and a normal pulmonary capillary wedge pressure. Historically, moderate to severe pulmonary hypertension has been viewed as a contraindication for liver transplantation due to the high risk of postoperative mortality. For patients exhibiting a right ventricular systolic pressure greater than 45 mmHg on preoperative echocardiography, right heart catheterization is advised. While newer or smaller-volume centers may be reluctant to proceed with transplant in patients with moderate pulmonary arterial hypertension, some larger, experienced centers have begun to accept these patients and report satisfactory postoperative outcomes [11].

Patients undergoing liver transplantation may experience significant hemodynamic fluctuations during the intraoperative period. These fluctuations are particularly notable during the drainage of ascites, manipulation of the liver, clamping of major vessels such as the inferior vena cava or portal vein, acute major bleeding, and reperfusion of the grafted liver. Intraoperative hypotension and inadequate fluid management can accelerate the postoperative risk of complications, including acute kidney injury, the need for renal replacement therapy, poor graft function, graft failure, and sepsis. These complications can lead to increased morbidity and mortality among recipients [12-14]. Various monitoring parameters and devices are utilized during liver transplantation, including invasive blood pressure monitoring, pulmonary artery catheters, arterial pulse wave analysis (measuring pulse pressure variation [PPV] and stroke volume variation [SVV]), and transesophageal echocardiography (TEE). Each of these monitoring tools has its advantages and disadvantages. Therefore, perioperative hemodynamic monitoring should be tailored to the individual, taking into account the availability of equipment, patient-specific factors, and the knowledge and experience of the operator.

Although the pulmonary artery catheter (PAC) has been considered the gold standard for cardiac output (CO) monitoring, its utility for fluid management during liver transplantation has been challenged by numerous studies. Central venous pressure (CVP) and pulmonary artery occlusion pressure, when measured with a PAC during liver transplantation, have shown poor correlation with cardiac index or stroke volume index [15,16]. Consequently, the use of PAC in liver transplant surgery is generally reserved for patients with pulmonary hypertension, where monitoring pulmonary artery pressures is essential. Minimally invasive techniques, such as PiCCO, LiDCO plus, or EV1000/Vigileo, can estimate CO by analyzing pulse waves. However, these methods are not considered reliable in patients with advanced cirrhosis. A poor correlation between CO measurements obtained through pulse wave analysis and those obtained via PAC thermodilution techniques has been documented in patients undergoing liver transplantation [17,18]. Pulse wave analysis techniques also measure SVV and PPV, which can indicate fluid responsiveness during surgery and in the critical care setting. In the context of liver transplantation, both SVV and PPV have been identified as good predictors of preload, specifically the right ventricular end-diastolic volume index [19,20]. However, there are several confounding factors that can affect these measurements, including spontaneous ventilation, a tidal volume less than 8 mL/kg, an open thorax, high positive end-expiratory pressure, and arrhythmias. These factors must be considered and addressed during monitoring.

Intraoperative TEE enables the rapid diagnosis of life-threatening conditions such as pulmonary thromboembolism, right ventricular failure, and regional wall motion abnormalities. It also provides a visual estimation of preload and ventricular function, which assists in guiding the administration of fluids and cardiac medications, including inotropes and vasopressors. Additionally, TEE offers real-time imaging of the hepatic and portal veins, allowing the direct visualization of any stenosis or thrombosis at the anastomosis site [21,22]. Although the routine use of TEE is on the rise among transplant centers, its application remains limited by the need for technical expertise, operator dependency, and the risk of bleeding, particularly in patients with grade 3 or 4 esophageal varices [23].

During liver transplantation, aiming for a low CVP (<5 mmHg) to guide fluid administration can decrease intraoperative transfusion requirements. However, this practice is associated with an increased risk of postoperative renal failure. Conversely, a high CVP (>10 mmHg) is linked to a greater incidence of postoperative respiratory complications, longer intensive care unit stays, and higher mortality rates [24,25]. Recently, a moderately restrictive fluid therapy approach, combined with maintaining a mean arterial pressure >60–65 mmHg, has been recommended to reduce blood loss during the dissection phase. This can be achieved by maintaining a subnormal CVP (5–7 mmHg) and administering mild to moderate doses of vasopressors. Clinical consequences typically associated with hypervolemia, such as increased blood loss, the need for transfusions, and postoperative respiratory complications, are minimized with this approach, and there is no increased risk of acute kidney injury [26].

The choice of fluid—whether crystalloids or colloids—continues to be a topic of debate. Crystalloid options include 0.9% saline, 0.45% saline, dextrose in normal saline, and balanced salt solutions (such as Ringer's lactate or Plasmalyte-A), each with its own benefits and limitations. In patients with preoperative hyponatremia, administering a large volume of 0.9% saline can cause a rapid increase in serum sodium levels, potentially leading to osmotic demyelination syndrome. Additionally, hyperchloremia from saline has been implicated in causing acidosis, hyperkalemia, and a decrease in the glomerular filtration rate due to afferent renal vasoconstriction. Ringer's lactate is typically avoided because of the risk of lactic acidosis and its potential to interfere with the assessment of a newly implanted graft. Most transplant centers prefer balanced salt solutions with low chloride content, which offer advantages such as acetate as a nonhepatic metabolized buffer, physiological chloride levels, and iso-osmolarity. However, a recent high-quality, multicentric, randomized trial comparing balanced salt solutions with saline found no difference in 90-day survival or kidney injury, despite the expected increase in serum sodium levels in the saline group [26,27].

The preferred choice of colloid solution—starch gelatin or albumin—for the perioperative period remains a subject of debate, with transplant anesthesiologists adopting varying practices. Numerous studies have identified the detrimental effects of starches in perioperative and intensive care settings. Starches have been associated with an increased risk of postoperative acute kidney injury and coagulopathy, suggesting they are best avoided. Conversely, human albumin has been shown to reduce the total intravenous fluid requirement, the incidence of pulmonary and interstitial edema, postreperfusion syndrome, vasopressor requirements, and mortality. However, its widespread use is limited by the high cost, particularly in low-income countries [26].

Packed red blood cells (PRBCs) and blood products such as fibrinogen concentrate, fresh frozen plasma, cryoprecipitate, and platelet concentrate must be reserved in advance of liver transplantation to ensure their availability when needed. The emerging theories on coagulation in patients with ESLD have shifted the paradigm concerning their bleeding tendencies. "Rebalanced coagulation" describes a delicate equilibrium between reduced levels of procoagulant and anticoagulant factors. The utility of traditional coagulation parameters (prothrombin time [PT]/international normalized ratio [INR], activated partial thromboplastin time (aPTT), and fibrinogen) in perioperative coagulation management is debated due to their static nature, the time and resources required for testing, and their poor correlation with surgical bleeding. The use of point-of-care viscoelastic coagulation tests, such as thromboelastography or rotational thromboelastometry, has been shown to decrease perioperative transfusion requirements. These tests are now routinely incorporated into intraoperative coagulation management at most centers [28]. Studies have demonstrated that while perioperative point-of-care coagulation monitoring during liver transplantation can reduce the transfusion of red cells and other factor concentrates, it does not confer any benefit in terms of survival or other outcomes [29,30].

Despite elevated PT/INR levels and reduced platelet counts, many patients with acute or chronic liver disease exhibit normal ranges on viscoelastic tests. This aligns with the concept of rebalanced hemostasis, allowing these individuals to undergo liver transplantation without the need for blood product transfusions. Additionally, these tests can reveal further details such as hypercoagulability, a prothrombotic state, and the presence of endogenous heparinoids, which are associated with vascular endothelial damage [31]. No correlation was found between bleeding and coagulation defects. Consequently, prior to liver transplantation, correcting coagulation defects with plasma is deemed neither beneficial nor necessary [32]. Furthermore, plasma transfusion aimed at correcting coagulation defects does not reduce the need for intraoperative red cell transfusions during liver transplantation and may, in some cases, have the opposite effect [33].

Tranexamic acid appears to be effective in reducing the need for red blood cell transfusions without increasing the incidence of thromboembolic events across a broad spectrum of liver transplant recipients. This includes patients at low risk of intraoperative bleeding as well as those at high risk of complications such as thromboembolism. There is no indication that the use of tranexamic acid elevates the risk of thrombotic complications [34].

To date, no transfusion guidelines have been established for liver transplantation. However, bleeding during these procedures has significantly declined over time, enabling the performance of transfusion-free liver transplants. Synthetic factors, such as prothrombin complex concentrate, fibrinogen concentrate, and antifibrinolytics, are increasingly being used as alternatives to the transfusion of blood and blood products. Administering platelets in the absence of bleeding or clinical coagulopathy may actually elevate the risk of adverse outcomes [34].

In patients with acute liver failure (ALF), cerebral edema is present in nearly 80% of cases, leading to increased intracranial pressure (ICP) [35]. As edema worsens, the grade of encephalopathy also increases. Several mechanisms have been suggested to contribute to the development of brain edema, including cytotoxic edema and astrocyte swelling, ammonia-induced toxicity with resultant oxidative stress, and neuroinflammatory mediators such as interleukins and tumor necrosis factor alpha [36-39]. More recent studies incorporating radiological imaging have identified the coexistence of interstitial and cytotoxic brain edema, which contributes to vasogenic edema and ultimately compromises the blood-brain barrier [40,41].

ICP monitoring (ICPM) in patients with ALF is a subject of debate. The use of an invasive ICPM device may increase the risk of intracranial hemorrhage due to the coagulopathy often present in these patients. Conversely, ICPM is essential to avert the adverse effects of increased ICP. ICPM can be performed using either invasive or noninvasive techniques. Invasive ICPM is considered the gold standard, but it is associated with a significant risk of hemorrhage—occurring in 10%–20% of cases and proving fatal in 1%–5%—as well as a risk of infection, which ranges from 0% to 7% in patients with ALF due to their compromised coagulation profiles [42,43]. Noninvasive methods, which include measuring the optic nerve sheath diameter via ultrasonography and employing transcranial Doppler, are available. However, current evidence suggests that these non-invasive techniques do not yield accurate or reliable measurements [44].

The Brain Trauma Foundation guidelines are widely accepted but are specifically tailored to patients with traumatic brain injury. In contrast, there is a notable lack of comprehensive guidelines for ICPM in patients with nontraumatic brain injuries. A recent review of the literature has underscored this gap, pointing out the absence of a uniform consensus on ICPM for patients with ALF [45]. The American Association for the Study of Liver Disease (AASLD) 2005 guidelines suggest considering ICPM primarily for patients on the transplant list. In the absence of ICPM evidence, these guidelines recommend regular assessments to detect signs of intracranial hypertension and to facilitate the early identification of uncal herniation, assigning an evidence level of III [46]. The AASLD's updated 2011 guidelines introduced the possibility of using recombinant factor rVIIa [47]. The United States Acute Liver Failure Study Group (ALFSG) in 2007 reported insufficient data to endorse routine ICPM for all cases of ALF. Nevertheless, it was noted that many ALFSG members opted for ICPM in patients with advanced (stage III/IV) hepatic encephalopathy [48]. The European Association for the Study of the Liver 2017 guidelines provided a level II-3 evidence and a grade 1 recommendation, advising that ICPM should be considered for a carefully selected subset of patients. This includes those who have progressed to grade 3 or 4 coma, are intubated and ventilated, and have a high risk of intracranial hemorrhage. The guidelines also recommend ICPM for patients presenting with one or more of the following criteria: young age with acute or hyperacute onset; ammonia levels exceeding 150–200 µmol/L that do not respond to initial treatments such as renal replacement therapy and fluids; renal impairment; and the need for vasopressor support [49].

Mendoza Vasquez et al. [45] published an account of their single-center experience with ICPM, utilizing an intraparenchymal modality following coagulation correction guided by viscoelastic testing. Nevertheless, the evidence provided by a single-center study for the use of ICPM is generally not considered robust [45]. To date, there is a lacuna in the available literature regarding the placement of ICPM devices in ALF patients and further studies are needed to establish the use of monitoring modalities in ALF patients.

Fast-tracking and early extubation in liver transplant surgery have been associated with improved graft function, reduced hospital stays, and lower overall costs. Currently, nutritional assessment, oral carbohydrate and protein supplementation, and the employment of a portocaval shunt are recommended practices in liver transplantation surgery [50].

Many centers now favor fast-tracking due to its ability to reduce patient discomfort and decrease ventilator-related complications. Factors that support early extubation include transfusion of fewer than five units of PRBCs, a low preoperative Model for End-stage Liver Disease score, reduced inotrope requirements, an optimal graft-to-recipient weight ratio, lower blood lactate levels, and shorter surgical duration [51]. Various studies from different centers, encompassing both adult and pediatric patients with diverse practices, have concluded that early extubation is both safe and cost-effective [52].

Perioperative care for liver transplant patients has undergone significant changes over the past few decades due to advancements in surgical and anesthesia techniques. The introduction of new monitoring tools for hemodynamics and coagulation, along with novel pharmacological agents, fluids, and perioperative protocols, has enhanced patient care and expedited recovery. However, there remain some gray areas where perioperative management practices differ among transplant centers, highlighting the need for the development of standardized protocols to ensure uniformity.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Author Contributions

Conceptualization: SM, VKG. Data curation: MB, PS, GRN. Formal analysis: SK, SKD. Visualization: VKG. Writing–original draft: SM. Writing–review & editing: SM, PS, VKG, GRN, SKD, AV. All authors read and approved the final manuscript.

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