Enhanced Recovery after Surgery (ERAS) Protocols in Liver Transplant Recipients—Challenges and Strategies for Implementation: A Review Article

Abstract

Background:

Implementing enhanced recovery after surgery (ERAS) protocols has revolutionized perioperative care across surgical specialties, significantly improving outcomes and reducing healthcare costs. The sheer complexity of liver transplantation makes it one of the most challenging surgical cases, technically as well as logistically. The use of ERAS protocols in liver recipients has been scarce, with significant interinstitutional variability.

Methodology:

We conducted PubMed searches to find relevant articles. We considered review articles, clinical trials, observational studies, and case-control studies.

Results:

ERAS in liver transplant surgery aims to optimize recovery, improve outcomes, and reduce the physiological impact of surgery through evidence-based practices. Each liver transplant case is unique, and ERAS protocols must be customized based on the patient’s underlying condition, donor characteristics, and surgical specifics.

Keywords

Enhanced recovery after surgery liver transplantation postoperative outcomes

Introduction

Perioperative management of liver transplantation has evolved over the last six decades with better outcomes, decreased morbidity and mortality and improved patient comfort.^[1] However, the burden of chronic liver disease, which results in around 2 million annual deaths worldwide, continues to increase.^[2] As the indications for liver transplantation seem to expand, the demand for liver transplantation is predicted to increase by 10% in 10 years. The total weighted treatment costs will rise 50% in the next 20 years.^[3] The need to implement enhanced recovery after surgery (ERAS) protocols in liver transplantation stems from the anticipated increase in patients undergoing the procedure and the burden of increasing procedural costs.

The concept of ERAS was contrived in the 1990s,^[4] bolstered by advancements in minimally invasive surgery short-acting anaesthetic agents and regional anaesthesia techniques.^[5] ERAS is a multimodal evidence-based programme aimed at minimising response to surgical stress and reducing the incidence of perioperative and postoperative complications, resulting in a shorter length of hospital stay without increasing readmission rates.^[6] Implementation of ERAS has been successfully demonstrated across various surgical domains like colorectal,^[7] oncosurgery,^[8] gynaecological^[9] and hepatic surgeries.^[10]

Liver transplant surgery offers unique specific challenges in implementing ERAS protocols like preoperative frailty,^[11] delirium,^[12] prolonged surgical time, high perioperative transfusion requirements^[13] and use of postoperative immunosuppression.^[14] Due to the above factors, implementation of ERAS in liver transplants has been scarce, with various institutes adopting individualised protocols with varying success. This narrative review will briefly discuss the components of ERAS in liver transplantation, along with challenges related to its implementation. Between 2000 and 2023, PUBMED articles were searched with TRANSPLANTATION and ERAS and LIVER TRANSPLANTATION, revealing 230 results. One hundred seventy-one full-text articles were assessed for eligibility, out of which 98 articles were found to be unrelated. The authors studied the remaining 73 articles, and the recommendations were compiled.

Which subset of patients undergoing liver transplantation can be considered for ERAS?

While institutions and clinicians for liver transplantation have widely accepted ERAS protocols, the eligibility and criteria may vary among institutions. However, some general considerations to identify patients who may benefit from an ERAS approach include the following:

1.1 Willingness and compliance: The willingness of the patient to participate in an ERAS protocol is essential. This includes active engagement in preoperative education and willingness to adhere to postoperative care instructions. The presence of hepatic encephalopathy might complicate the implementation of ERAS protocols. However, patients with grade 1 and 2 hepatic encephalopathy could be considered part of the programme. An area that is more often overlooked is the social and psychological support available for the patient. A thorough assessment of these factors must be assessed before the surgery.

1.2 Functional and nutritional status: The presence of sarcopenia^[14] and malnutrition needs to be ruled out, and adequate measures must be taken to optimise the patient’s nutritional status. Multimodal prehabilitation^[15] has emerged as an innovative approach to optimise the physiological capacity of the recipient.

1.3 Absence of cardio-pulmonary dysfunction: Cardio-pulmonary dysfunction might complicate the implementation of ERAS due to increased risk of perioperative complications, challenges in fluid management, special considerations in perioperative analgesia and impaired exercise tolerance. Tailoring the protocol to each patient’s needs and risks is crucial for optimising outcomes in cardio-pulmonary dysfunction.

1.4 Satisfactory graft function: Graft function^[16] plays a crucial role in the overall success of liver transplantation and influences the process of enhanced recovery after the procedure. A graft with a low degree of steatosis^[17] (<30%), optimal volume^[18] (graft-to-recipient weight ratio [GRWR] > 0.8), good preservation techniques and surgical expertise are crucial for the success of liver transplantation. Adequacy of the graft function should be confirmed by demonstrating resolution of acidosis, correction of liver enzymes and improvement in the overall functional and cognitive capacity of the patient.^[19]

Overall, most of the principles of ERAS protocol can be safely implemented in most cases undergoing liver transplantation except those in acute and acute chronic liver failure with features of raised intracranial pressure. Implementing ERAS principles has improved postoperative outcomes across all surgical specialties. The ERAS protocol can be modified or deviated according to the individualised clinical needs of the patient collaboratively by the surgical team, anaesthesiologists and other relevant healthcare professionals.

Enhanced recovery of the liver recipient

Inspired by the success of ERAS protocols in other surgical specialties, many transplant centres apply aspects of enhanced recovery in their perioperative management. It has been proven beyond doubt that short-term complications like ventilator-associated pneumonia,^[20] acute kidney injury,^[21] ileus^[22] and biliary complications^[23] result in poor allograft survival and aggravate morbidity and mortality. Incorporating principles of ERAS is bound to decrease the incidence of short-term postoperative complications, which will aid in improving outcomes after liver transplantation.

2.1 Preoperative measures

The preoperative evaluation should include a thorough review of the patient’s comorbidities, both associated and independent of liver failure. The majority of the patients with chronic liver disease are physically deconditioned at the time of liver transplantation. Sarcopenia and frailty^[24] are seen in approximately half of the patients coming for transplant. Optimising nutritional status preoperatively is essential for minimising complications and enhancing recovery. Scoring systems like the Karnofsky performance index,^[25] liver frailty index^[26] and abdominal muscle mass on computed tomography^[27] can be used to risk-stratify these patients when implementing ERAS pathways.

The European Association for the Study of the Liver Guidelines on Nutrition has a high prevalence of malnutrition manifesting as undernutrition or obesity in patients with chronic liver disease.^[28] Three randomised control trials published on preoperative nutritional interventions showed no difference in short-term outcomes between the intervention and control groups.^[29-31] We believe that targeted preoperative interventions like vitamin D supplementation and ensuring the caloric and protein requirements have a limited potential for harm and a high potential to translate into better postoperative outcomes.

Optimising chronic medical conditions preoperatively is crucial in improving surgical outcomes. This should consist of a multidisciplinary team, including surgeons, anaesthesiologists, hepatologists and other specialists. Features of hepatic decompensation need to be addressed and treated as and when necessary. There is no evidence supporting preoperative correction of coagulopathy until and unless the patients show clinical features of deranged coagulation.

Cardio-pulmonary screening is of particular importance in patients undergoing liver transplantation. In addition to common cardiac pathologies like coronary artery disease and valvular pathologies, these patients have a high incidence of diastolic dysfunction and electrophysiological abnormalities. Identification of these conditions preoperatively is essential as it poses significant morbidity in the setting of stressful conditions like liver transplantation. Sonological imaging of the lungs is necessary to rule out the presence of hepatic hydrothorax, which can be managed with salt restriction and diuretics.

Particular emphasis should be placed on screening for infections due to the immunoparetic state in these patients. Prophylactic antibiotics should be considered along with antiviral prophylaxis in the case of hepatitis B and C. With antibiotic resistance increasing worldwide, screening for multidrug-resistant pathogens like carbapenem-resistant Enterobacteriaceae (CRE) should be part of the preoperative evaluation. Renal insufficiency should be evaluated using markers of kidney injury like cystatin C, NGAL and KIM whenever possible, along with a sonological examination. Cautious volume expansion coupled with splanchnic vasoconstrictor therapy might benefit selected patients.

A psychosocial assessment is crucial in these patients as depression is reported at rates of 17%-57% and anxiety at similar rates of 19%-55%.^[32] Targeted psychosocial interventions demonstrated better short-term outcomes^[33] following liver transplant with an adherence to treatment plan and a lower rate of graft rejection. Counselling the patient and assessing willingness to comply with deaddiction programmes for alcohol, smoking etc. is also strongly recommended.

Preoperative fasting requirements in these patients are similar to other surgical procedures with six hours of fasting for solids and two hours for clear fluids. Prolonged fasting is not recommended. We did not get any evidence suggesting the use or disuse of preoperative carbohydrate loading in patients undergoing liver transplantation.

2.2 Intraoperative measures

Anaesthetic measures

An optimal anaesthetic regimen is essential for enhanced recovery and for improving short-term outcomes following liver transplantation. The goal of anaesthetic management must focus on early extubation, good postoperative analgesia and less respiratory depression. It has been taught traditionally that the requirement for anaesthetic agents is less in patients undergoing liver transplantation as opposed to the standard surgical population.

The use of the bispectral index or similar monitors of the depth of anaesthesia might help decide on the dose of inhalational agents as well as opioids. Short-acting opioids will have obvious benefits in enhancing recovery. We believe that following an optimal opioid dosing strategy with reductions in the dose during the anhepatic phase will allow enhanced recovery irrespective of the agent used. Traditionally, benzylisoquinoline was used to be the neuromuscular blocking agent of choice due to its extrahepatic metabolism.^[34] But with the advent of sugammadex.^[35] routine use of vecuronium or rocuronium can also be considered.

Regional anaesthesia, especially neuraxial techniques, has traditionally been approached with caution owing to inherent coagulopathy associated with chronic liver disease patients. However, there is growing interest in exploring the role of regional anaesthesia^[36,37] in this setting, particularly for its potential benefits in postoperative pain management, reduced opioid consumption and better haemodynamic stability. We routinely use transversus abdominis plane (TAP) blocks in liver recipients with no significant coagulopathy. These blocks avoid the risks associated with neuraxial techniques while providing excellent intraoperative analgesia, aiding in faster postoperative extubation.

Judicious administration of intraoperative fluids is essential to prevent postoperative complications. Sustained hypervolemia without fluid responsiveness and elevated filling pressures should be avoided. Fluid administration can be guided by minimally invasive cardiac output monitors depending on the patient’s needs and the expertise of the anaesthetic team. Empirical correction of coagulation should be discouraged; instead, blood products should be administered based on viscoelastic methods coupled with clinical judgment.^[38]

Each patient undergoing a liver transplant must be screened for eligibility for early extubation (within 3-8 hours of surgery). The eligibility should depend on the clinical status of the patient as well as the local resources available for monitoring. Many studies have shown that early extubation after liver transplantation is associated with improved short-term outcomes.^[39] There are no set guidelines as to when not to conduct early extubation. However, certain factors preclude early extubation in our institute, which include ongoing transfusion requirements > 2 units per hour, significant vasoplegia, significant preoperative hepatic encephalopathy, acute liver failure, preoperative mechanical ventilation and ambiguity in the adequacy of graft function as evidenced by increasing trend of serum lactates.

Surgical measures

Surgical techniques must be refined with a short operating time, less blood loss and strategies to reduce cold ischaemia time. Routine use of venovenous bypass is not recommended.^[40] Portocaval shunt can be considered when a prolonged anhepatic phase is anticipated. Organ perfusion techniques aim to reduce damage during organ retrieval, preservation and reperfusion. These machine perfusion techniques also help prevent postreperfusion syndrome and early allograft dysfunction,^[41] availability depending on their local availability, machine perfusion techniques should be considered for all grafts. The use of cell salvage can be regarded in cases where massive transfusion is expected.^[42]

2.3 Postoperative measures

The postoperative care of liver transplant recipients is complex and requires a coordinated, multidisciplinary approach to ensure optimal outcomes. Liver transplant patients face many challenges, including graft function monitoring, immunosuppressive therapy management, infection control and overall recovery. Integrating various specialties like surgeons, intensivists, hepatologists, anaesthetists, physiotherapists, dieticians and infectious medicine specialists is crucial for holistically addressing these challenges. Each team member brings specialised expertise that, when integrated, results in comprehensive care.

Execution of ERAS post-liver transplant becomes complicated and challenging due to the multitude of factors in play, like ambiguity in deciding optimal intravenous fluid therapy, immunosuppression, difficulties in practicing multimodal anaesthesia and difficulties in practicing early removal of invasive catheters along with surgical drains. Patients with end-stage liver disease also have an increased susceptibility to infections, which will directly affect the efficacy of enhanced recovery protocols. In addition to the factors mentioned above, several clinical dogmas exist among the practitioners of liver transplant, which need to be overcome for the successful implementation of an ERAS programme.

Enhanced recovery protocols traditionally advocate the judicious use of intravenous fluids and the prevention of hypervolemia. Most transplant centres prefer relative hypervolemia in the early postoperative period to prevent the incidence of thrombotic events which may be precipitated by hypovolemia. Recent studies counter this assumption with a higher incidence of hepatic artery thrombosis in patients with a higher cumulative positive balance.^[43] Normalising biochemical values like serum lactate and central venous saturation as evidence of normovolemia may also result in overfilling these patients.^[44] We recommend performing a haemodynamic ECHO cardiogram on arrival for all liver transplant patients to guide fluid therapy.

Unlike other surgeries, the adequacy of postoperative analgesia is often overlooked in liver transplantation due to the routine drill of delayed extubation and mobilisation. Implementing enhanced recovery protocols calls for a multimodal analgesic regimen that enhances patient comfort, facilitates early mobilisation and ultimately contributes to rapid recovery. While prescribing postoperative opioids, one needs to be mindful of the significantly lower requirement of opioids in these patients compared to the other surgical population.^[44] This is mainly seen in patients with increased model for staged-stage liver disease (MELD) scores and those with severe hypoalbuminemia. Due to its established safety profile, absence of sedative effects and lack of nephrotoxicity, paracetamol is a reasonable option for postoperative analgesia. The use of subcostal TAP block has been associated with reduced morphine consumption and earlier withdrawal from mechanical ventilation.^[45]

Early removal of indwelling catheters and surgical catheters remains a challenge in liver recipients. It will depend on patient and graft-related factors like the need for vasopressors and ongoing ascitic drainage. Studies have reported a high incidence of catheter-related bloodstream infections in liver transplant unit bloodstream infections in liver transplant units, which can significantly affect short-term outcomes.^[46] Strict adherence to standard infection control practices, along with the use of antibiotic-coated central lines, will help counter this problem. In the setting of liver transplantation, no studies pertaining specifically to the timing of indwelling catheters and drains exist. However, aggressive early removal can be practiced if patient conditions permit.

The intrinsic immunodeficiencies coupled with the administration of immunosuppression make these patients more vulnerable to postoperative infections. Besides the risk for sepsis, opportunistic infections like cytomegalovirus can cause graft rejection with vascular and biliary complications. Prophylactic antibiotics for postoperative bacterial infections should be guided by local antibiograms with de-escalations whenever feasible. Universal prophylaxis against cytomegalovirus is beneficial depending upon the sero status of the donor and recipient. Antifungal therapy is also strongly recommended for liver transplant recipients who are at high risk of developing invasive fungal infections.^[47]

Implementation of early enteral nutrition and mobilisation^[48] are crucial to the success of any enhanced recovery programme. This is of particular importance in chronic liver disease who are nutritionally and physically deconditioned. Some centres practice the removal of nasogastric tubes during the reversal of anaesthesia. Still, caution needs to be exercised in the presence of hepatic jejunostomy and cases with extensive bowel handling. Oral nutrition can be initiated within 12-24 hours post-transplant. Parenteral nutrition should be started only as a last option when enteral nutrition fails to meet caloric requirements. Mobilisation should be encouraged when the patient is off vasopressor support with early goal-directed interventions. Physical rehabilitation may be continued after discharge as well.

The length of stay after a transplant is an essential benchmark for the quality and efficacy of care. We could identify six studies that looked at an optimal time to discharge patients after liver transplantation.^[49-54] As a general recommendation, discharge can be done as early as on the eighth postoperative day in low-risk patients and centres with a robust follow-up system. The centre must design educational programmes to increase patients’ awareness and knowledge of immunosuppression and changes after liver transplant. Also, a systemic audit improves compliance and clinical outcomes in healthcare practice.^[55]

Is enhanced recovery possible after a paediatric liver transplant?

It has been customary to ventilate paediatric liver recipients for a few days postoperatively due to the presence of a high graft-to-recipient ratio and increased incidence of vascular complications.^[56] Recently, with the refinement of surgical techniques like graft reduction^[57] coupled with improvements in anaesthesia and paediatric intensive care, a few centres have started performing early extubation after liver transplantation. Even though there are not any meta-analyses studying the effectiveness of ERAS protocols in paediatric liver transplantation, published reports of early extubation leading to shortened intensive care unit (ICU) stays are plentiful.

Fullington et al.^[58] reported a series of 84 patients who underwent paediatric liver transplantation over six years. They noted a doubling of the number of on-table extubations during the last three years, with a reduced ICU stay and reintubations. However, the article failed to elaborate on their institute’s surgical and anaesthetic methods. A more recent report by Sahinturk et al.^[59] reports that early extubation was performed in 48% of their paediatric liver recipients, and a successful demonstration of reduced ICU stay was observed. The authors reported a case series of 16 paediatric patients below the age of two years who were extubated immediately following liver transplantation. We performed a right subcostal TAP block with bilateral rectus sheath block following wound closure, which helped in reducing opioid consumption and improved patient comfort postoperatively.^[60]

Enhanced recovery protocols can be successfully implemented in paediatric liver recipients. Improvements in paediatric anaesthesia with the implementation of myofascial blocks, along with advancements in paediatric intensive care like high-frequency nasal cannulae, will help in reducing the duration of postoperative ventilation. Certain aspects that can further help in the implementation of ERAS in paediatric transplant would be preoperative nutritional therapy, implementation of point-of-care ultrasound postoperatively and encouragement of parental involvement in postoperative care.

Conclusion

Even though many centres are unacquainted with ERAS protocols, implementing ERAS protocols can potentially improve perioperative outcomes in liver transplantation. This surgery poses particular intrinsic challenges that make implementing enhanced protocols difficult. Clinicians in perioperative care can tailor individualised protocols according to the centre and patient. This review presents a comprehensive and current overview of relevant areas related to enhanced recovery of liver transplant recipients. The success of any ERAS programme will need a multimodal team approach working towards reducing short-term complications, enhancing patient comfort and ultimately translating to improved outcomes.

Abbreviations

ERAS: Enhanced recovery after surgery; GRWR: Graft-to-recipient weight ratio; MELD: Model for staged-stage liver disease; TAP: Transverse abdominis plane

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

Institutional ethical Committee approval number

Not required.

Credit author statement

VS: Concept, drafting and editing.

CC: Editing.

SC: Editing.

Data availability

No data was analysed.

Use of artificial intelligence

Artificial Intelligence was not used in preparation of this article.

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