Enhanced recovery after liver transplantation—a prospective analysis focusing on quality assessment

Introduction

Enhanced Recovery Programs (ERP) or so called Fast-tracking or Enhanced Recovery after Surgery (ERAS) for complex liver surgery led to a significant reduction in perioperative stress, postoperative complications, faster functional recovery, shorter hospital stays and reduced costs (1). The successful application of ERP/ERAS in liver surgery evoked the application of ERAS in liver transplantation (LTx) (1,2). In the 1990s, elements of ERAS were introduced to LTx by Rossaint et al. (3,4). A key element in this development was the introduction of Fast-Track Liver Anesthesia using predefined criteria such as transfusion amount, baseline comorbidities and lab values to support individualized decisions for early extubation in order to achieve shorter intensive care unit (ICU) stays (5). Since then, several parameters, such as preoperative nutrition, anesthesia management, early mobilization, feeding and optimal analgesia of patients undergoing LTx, were introduced to ERAS programs (6). Meanwhile, a number of studies have demonstrated that ERAS in LTx is safe and effective and has potential in improving recipient outcomes and optimizing resource utilization, as well as improving patient satisfaction. For instance, Feizpour et al. reported that an ERP for LTx was associated with a shorter median ICU and hospital stay, as well as a significant reduction in median direct cost per case (7). A publication by Xu et al. reported a significant reduction of the postoperative hospital stay in favor of the ERAS group (14.5 vs. 16 d; P<0.001) (8). “Guidelines for Perioperative Care for Liver Transplantation: Enhanced Recovery After Surgery (ERAS) Society Recommendations”, have been drafted by Brustia et al. in 2022 and reviewed by a wide international panel of experts applying the Delphi method (6,9). Due to the lack of a standardized ERAS protocol and inclusion criteria of LTx patients, the authors of the publication recognized that there lacks strong evidence in ERAS in LTx (6). Therefore, the value and potential developments of ERAS should be further investigated for liver transplant patients.

In this context, we describe an ERP/ERAS in LTx in our center in China based on previous experience in the past decades. There were several confounding factors in the introduction of an ERP/ERAS protocol, acknowledging the types of donors [donation after controlled circulatory death (DCD), donation after brain death (DBD), donation after brain and cardiac death (DBCD)], aspect of regional donation, training of anesthesia in order to provide Fast-Tracking Anesthesia, training of ICU staff as well as training of senior and junior members of the team becoming aware of rapid changes in patients after major surgery exposed to immunosuppression in recipients displaying different health and physiological features due to their primary disease as well as their comorbidities. In addition we applied bench marks (death during operation, in-hospital mortality, postoperative hospital stay, 1-year survival) used in the Quality Assessment of liver transplant patients as used and reported by the Institut für Qualitätssicherung und Transparenz im Gesundheitswesen (IQTIG) in Germany (10). We present this article in accordance with the STROCSS reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-349/rc).

Methods

ERAS protocol

An ERAS protocol had been previously developed and implemented, based on standard operating procedures (SOPs) generated in Halifax, NS, Canada, at the QEII Clinic and the UKE in Hamburg, Germany between 2003 and 2017. The ERAS Protocol was separated in (I) preoperative management, (II) perioperative management including donor, operation, anesthesia and intraoperative management. This protocol was developed and implemented for LTx in our center between 2018–2021. Likewise, we used this protocol in analogy in ultra-radical surgery for ovarian cancer in collaboration with the Department of Gynecology (11).

Donor and patients

All transplantations and organ donations were approved by the hospital ethics committee of The First Affiliated Hospital of USTC and in accordance with the Declaration of Helsinki (as revised in 2013) and the Declaration of Istanbul. Written informed consent of each patient was given before operation. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of the USTC, within University of Science and Technology of China (2024-RE-107). From January 1, 2021 to December 31, 2022, 73 adult orthotopic LTx were performed in our center. Sixty-eight were enrolled in the prospective evaluation. Five patients who received second LTx (n=1), living donor liver transplantation (LDLT) (n=1), split LTx (n=1) or were discharged from the hospital against medical advice (n=2) were excluded from this prospective analysis.

Preoperative management

The ERAS protocol includes preoperative, perioperative, and postoperative guidelines and SOPs, which are shown in Tables 1-3. For preoperative management, a structured evaluation protocol prior to listing for LTx is done. Briefly, all potential patients for LTx are evaluated in the clinic of hepatobiliary surgery and transplantation. The standard assessment items for patients are provided in Table 1, including demographic data, primary liver disease, medical history, past history, family history, routine laboratory test, imaging test, Model for End-Stage Liver Disease (MELD) score etc. Personalized assessment is carried out in patients with uncommon liver disease or complex disease status. After completion of the assessment, indication for listings is discussed by a multidisciplinary conference with participation of doctors from hepatobiliary surgery and transplantation, infectious disease, gastroenterology and anesthesia. The multidisciplinary conference decides regarding eligibility for LTx and the potential recipient is listed at the China Organ Transplant Response System (COTRS). Meanwhile, detailed preoperative counseling is given and informed consent is signed. Once a donor liver is available and allocated, the recipient will be hospitalized for actual lab work-up and if needed actual imaging, counseling with anesthesia, solid food and liquid fasting for no more than 6 hours and no intestinal preparations prior surgery.

Perioperative management (donor, operation, anesthesia and intraoperative management)

All donor livers were from deceased donors (Table 4). LT was performed by full size orthoptic LTx. The anesthetic techniques were conducted as previously described (12). Briefly, propofol, fentanyl and succinylcholine were applied to facilitate rapid sequence induction of anesthesia and intubation; then, anesthesia was maintained with isoflurane. Muscular relaxation was maintained using cisatracurium. Fentanyl was reasonably administered so that the total dose did not exceed 10 µg/kg. The muscle relaxant was reversed with neostigmine and glycopyrrolate during closure of skin. During the operation, standard anesthesia monitoring was applied, including pulse oximetry, non-invasive blood pressure, temperature monitoring and warming devices were utilized to prevent hypothermia. The hemodynamic stability was continuously monitored, including the monitoring of invasive arterial blood pressure and central venous pressure (CVP) etc. Thromboelastography (TEG) test was carried out for viscoelastic testing and guiding effective utilization of blood product and antifibrinolytic agents. The detailed protocol for intraoperative management is presented in Table 2. The standard surgical technique is described elsewhere (13). During the anhepatic phase, 1.0 g methylprednisolone and 20 mg basiliximab were given. Basiliximab 20 mg was given again at postoperative day (POD) 4. On POD 1, a triple immunosuppressive regimen was started, consisting of tacrolimus bid (monitored according to C0 3–8 ng/mL), mycophenolate mofetil (MMF) (500 mg bid) and corticosteroids (100 mg qd, tapered to 5 mg at POD 7). Patients with hepatocellular carcinoma (HCC) were switched within one week following transplantation from MMF to sirolimus (C0 3–8 ng/mL).

Postoperative management

After operation, tracheal extubation was performed within 6 hours for all transplant patients in the ICU department. The gastric tube was removed within 48 hours after the transplant patients were transferred to the ICU department. During this course, the standard protocol of postoperative care, including physiological monitoring, food intake, laboratory, diagnostic imaging, stress ulcer prophylaxis, analgesia etc., was initiated the details of the postoperative management protocol are provided in Table 3.

Outcome

Assessment and comparison of outcome were done by using benchmarks from the German Institute for Quality Management and Transparency in Healthcare (IQTIG). These benchmarks were death during operation (0.89%), in-hospital mortality (11.01%), length of hospitalization (LOS) >41 days (24.86%), 1-year patient survival (82.02%) based on the year 2022 (14).

Data collection

Information regarding patients’ characteristics was collected, including age at transplant, gender, body mass index (BMI), MELD score, primary diagnosis, blood type. The operative and post-operative characteristics, including anesthetic time, operative time, anhepatic phase time, the volume of intraoperative blood transfusion and fluid transfusion, postoperative blood transfusion and ICU stay, postoperative hospital stay, morbidity (classified as Dindo-Clavien Classification) and mortality, were collected. Discharge criteria included closed incision, tolerance for regular diet, stable vital signs, and no complications. All patients were followed-up for 1 year.

Statistical analysis

Continuous variables normally distributed data were expressed as mean ± standard deviation (SD). All measurements and calculations were analyzed using GraphPad prism 8 (GraphPad Prism Software Inc., San Diego, CA, USA).

Results

Donor demographics

Mean age of the 68 donors was 47 years (range, 36–55.5 years) and 58 were male (85%). Cause of death was in 37 donors’ cerebral hemorrhage and in 21 craniocerebral trauma, in 6 cerebral infarction, acute organophosphorus pesticide intoxication, carbon monoxide inhalation, hypoxic-ischemic encephalopathy and one unknown were n=1 each. Blood type O was dominating with n=27 (39.7%) followed by A [17 (25%)], B [16 (23.5%)] and AB [8 (11.8%)]. Forty donors were DBD, 26 DCD and 1 donor was DBCD. Laboratory tests showed typical values for donors (Table 4).

Recipient demographics

A total of 68 patients who underwent LTx were included into the prospective evaluation of the ERAS protocol. Demography and general characteristics of recipients are presented in Table 5. Mean age of the patients was 49.6 years (range, 26–68 years) and the majority of patients (81%) were male. Mean BMI was 24 kg/m² (range, 15–37 kg/m²), mean MELD score was 15.4 (range, 6–39), 3 patients had an MELD score higher than 30. Hepatitis B virus (HBV) related cirrhosis was diagnosed in 53 recipients of whom 24 had in addition HCC; four more patients had HCC related to other primary diseases (Table 5). Five patients were diagnosed with alcohol related cirrhosis and primary biliary cirrhosis, autoimmune disease and drug induced cirrhosis, undefined cirrhosis, respectively. All patients with HCC were within the Milan criteria prior to transplantation and had received downstaging. Blood type A was present in 29, B in 17, AB in 9 and O in 13 recipients. The majority of recipients had cholecystolithiasis n=14 as comorbidity, hypertension was diagnosed in 7 patients and diabetes mellitus II in 6 patients. Spontaneous bacterial peritonitis had been diagnosed and treated prior to transplantation in 4 patients. At the time of transplantation none of the patients suffered from an infection.

Perioperative and postoperative outcomes

The perioperative and postoperative outcomes of patients are given in Table 6. All patients received blood products, such as packed red blood cells (PRBC) or fresh frozen plasma (FFP), to maintain circulatory stability intraoperatively in addition with crystalloids (mean 2,218.7 mL). A mean of 5.6 units of PRBC was given and 857 mL FFP. Twenty patients and 18 patients with platelet count less than 50×10⁹/L and prolonged prothrombin time received intra- and post-operatively platelet transfusion, respectively. The mean operation time in our cohort was 6.73 hours, and the average anhepatic phase time was 67.51 minutes. None of the patient suffered from intraoperative hypothermia. Tracheal extubation was performed in the ICU department within 6 hours post operation and subsequently the patients were transferred to the intermediate care (IMC) unit. Average stay in ICU/IMC was 4.6 days (range, 2–14 days), only one patient stayed longer than 9 days on the ICU. None of the patients required re-intubation. The immunosuppression was started on POD 1 with tacrolimus (3.8 ng/mL C0) in combination with MMF and rapid tapering of steroids by POD 7 to 5 mg/d. Basiliximab was given on POD 0 and 4, 20 mg intravenous (iv). One-week post-operation Tac C0 was 7.4±2.9 and at time of discharge 6.7±1.8 ng/mL. No episode of acute rejection was observed within the first 365 days. Sixty-six patients were discharged within 40 days after transplantation with a mean stay of 21.7 days in hospital, 2 patients [biliary stricture and portal vein (PV) stenosis (n=1), abdominal bleeding (n=1)] stayed longer than 41 days (Table 7) to a maximum of 53 days. Postoperative complications with a Clavien-Dindo classification (CDC) > II were seen in 16 patients (23.5%). Biliary strictures in terms of a stenosis of the anastomosis was documented in 9 patients and treated by endoscopic retrograde cholangiopancreatography (ERCP), dilatation and stenting. Pleural effusions were observed in 5 patients with associated atelectasis of the right lower lobe of the lung, followed by bronchoalveolar lavage (BAL) (n=1) and if necessary, antibiotic treatment based on antibiogram given by culture. Portal vein stenosis was observed in 2 patients and treated with angioplasty and stenting. Bleeding needing intervention (CDC IIIb) was diagnosed in two cases and controlled by surgical respectively radiological (coiling) intervention. No postoperative mortality was reported during the hospital stay, one patient was readmitted one week after an uneventful course and discharge due to an acute myocardial infarction of which he died. In his pretransplant workup, no evidence for cardiovascular disease had been diagnosed. In 28 patients with HCC histopathology confirmed Milan staging as T1–T2, N0, M0. Patients with HCC were switched from MMF to sirolimus at POD 7, maintaining C0 of 3–8 ng/mL with a C0 of 7.9±5.6 ng/mL at the time of discharge. These patients received in addition sulfamethoxazole prophylaxis for 3 months. Following discharge, 13 (19%) patients needed readmission (Table 6) for bile duct (BD) stenosis (n=3), PV and BD stenosis (n=2), acute myocardial infarction, pneumonia, HCC recurrence [increased alpha-fetoprotein (AFP)], cholangitis, PV stenosis, ischemic-type biliary lesion (ITBL), coronavirus disease 2019 (COVID-19) infection respectively craniocerebral trauma (each n=1).

Discussion

ERAS is by now a well-validated multimodal approach for almost all types of major surgical procedures, including liver surgery, colorectal surgery, thoracic surgery, urology, gynecology etc. (6). End stage liver diseases in China and western countries may differ in terms of underlying disease, comorbidities, metabolic stress response and organ-specific complications (15,16). To date, the application of ERAS in LTx is less reported in China. Therefore, it is unclear whether ERAS elements validated in western countries can be extrapolated and applied for LTx in China, hence we prospectively evaluated an ERAS protocol in our center with a focus on a patient related individualized approach and quality measures for outcome. One of the key factors in implementing ERAS protocols is the understanding of the philosophy behind ERAS by both patients and caregivers (17,18). The goal of the ERAS approach is to reduce the patients’ reaction to surgical stress, promote better utilization of medical resources and thus improve patient recovery and safety. Introduction of Fast-Track Anesthesia and the successful application of ERAS in abdominal surgery promoted the utilization in LTx. Since the early 1990s, different ERAS protocols in LTx have been developed and compared to conventional cares, indicating clear benefits, but showing at the same time the need for a more comprehensive approach (19). Independent studies have validated that preoperative nutrition, early mobilization and feeding, and particular optimal analgesia are helpful to improve quality of care with shorter ICU stay and hospitalization, associated with lower total treatment costs of patients undergoing LTx.

LOS is one of the critical issues a number of ERAS protocols are aiming for. Here we put a patient centered treatment into the foreground, focusing on the opportunity to safely discharge the patient and keeping the readmittance rate low. Our readmittance rate was 19% and mainly related to postoperative complications, developing after discharge.

Measuring outcomes in LTx so far has been done by registries looking into patient and graft survival. Here we choose to compare outcome parameters with benchmarks of the quality assessment in LTx used by the IQTIG in Germany. These benchmarks in 2022 are death during operation (0% vs. 0.89%), in-hospital mortality (0% vs. 11.01%), LOS >41 days (2.9% vs. 24.86%), 1-year patient survival (98.25% vs. 82.02%) (14). The primary approach using an ERAS protocol was to improve quality service for patients in combination with acknowledging particular features of Health services in China resulting in LOS comparable to e.g., Germany: (I) the ideas among medical staff and patients are profoundly traditional; (II) medical administrations do not consider the application of ERAS protocols as the status quo in the hospital, including every involved department; (III) the medical treatment costs are very low in China; (IV) patients from the countryside would prefer not to travel home after surgery and then return for laboratory and particular C0 levels a few days later or weekly in the early phase; (V) the ward beds are cheaper than stays in a hotel and safer for the observation of their conditions until the completion of the initial postoperative care; (VI) patients do not have family physicians in China and if they go home, local hospitals would deny their admission in the presence of any complications; and (VII) insurance companies only pay for hospitalization but not for the costs related to regular visits in clinic (11). Taken together, setting up a transplant center and providing quality care needs modified approaches based on social and cultural backgrounds in order to serve patients in their best interest.

Preoperative evaluation of liver recipients is of paramount significance before LTx and should start with a detailed history (medication history, family history and past history etc.) and physical examination. It should include not only the etiology and status of liver cirrhosis or failure, but should include all major organ systems, particularly renal, cardiac and pulmonary function (20,21). Therefore, for patients with end stage liver disease being waitlisted, essential tests are performed to determine the etiology of liver disease. Additional diagnostic imaging tests, such as ultrasound and contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI) particularly in HCC patients are essential and should follow Liver Imaging Reporting and Data System (LIRADS) procedures (19,22). In all 28 patients the radiology assessment was confirmed by pathology. A head MRI or CT scan should be given to rule out potential intracranial infection or bleeding, brain injury etc., especially for patients with previous extracorporeal liver support (23), or with a history of hepatic encephalopathy (24) or Wilson disease (25). Additionally, it has been reported that the prevalence of coronary artery disease in patients with liver cirrhosis is similar to those in the general population and cirrhotic cardiomyopathy shows a prevalence of approximately 50% in patients with chronic liver disease (26,27). Despite a specific evaluation we missed one patient being discharged at POD 15 after an uncomplicated postoperative course and readmitted with acute myocardial infarction one week later. Therefore, for patients with any history of cardiopulmonary diseases or other chronic ailments (such as diabetes, hyperlipidemia, and severe obesity etc.), an extensive evaluation should include the identification of potential cardiology and pulmonology diseases to make sure the patient can stand the operation. Non-curable extrahepatic malignancies are a contraindication for LTx (28), selective tumor marker tests and positron emission tomography-computed tomography (PET-CT) examination should be performed in patients with a history of malignancies other than HCC. Taken together, listing for LTx should be decided by a multidisciplinary team, including doctors from departments of hepatobiliary surgery and transplantation, anesthesia, infectious disease, gastroenterology, and if necessary, consultation from oncology, cardiology and radiology should be included.

In conventional abdominal surgery, providing information regarding the procedure and details of the patients’ postoperative tasks has been supportive in patient’s collaboration regarding perioperative feeding, mobilization and respiratory physiotherapy, and thus being helpful to reduce complications after abdominal surgery (29,30). For our center we extrapolated this knowledge to our liver transplant population and performed routinely a detailed and comprehensive preoperative consultation and education. Preoperative fasting, for liquids no more than 2 h and for solid food no more than 6 h prior surgery, has proven to be safe and is recommended for digestive surgery (31). In addition, some research indicated that carbohydrate intake before operation had less perioperative insulin resistance which may facilitate liver regeneration (32). Hence, recipients are given oral bowel preparation by solid food fasting for no more than 6 hours and liquid fasting for less than 2 hours before operation in our center.

Anesthesia management for LTx follows fast tracking protocols as recently summarized in guidelines (33). Key elements (Table 2) are a focus on hemodynamic, normothermia and coagulation monitoring including standard monitoring [electrocardiogram (ECG), pulse oximetry, non-invasive blood pressure and temperature], hemodynamic monitoring (CVP, invasive arterial blood pressure, pulmonary capillary wedge pressure, intraoperative fluid management), and neurologic monitoring (bispectral index monitoring anaesthetic depth), etc. (34,35). Hemodynamic instability during LTx is difficult to manage and associated with postoperative morbidity and mortality (36,37). Patients with liver cirrhosis have an abnormal fluid distribution and impaired response to fluid therapy (34,38). Inappropriate fluid supply during operation can have substantial adverse effects, including pulmonary and graft oedema, dilutional coagulopathy and thrombocytopenia, hypovolemia, leading to abnormal gas exchange, disturbance of blood coagulation. Therefore, haemodynamic monitoring, strict intraoperative fluid management and coagulation management is crucial during the whole procedure. As for coagulation management, viscoelastic testing, which reflects the interaction of plasma, blood cells, and platelets, is recommended during a LTx procedure (39). In our center, the mean arterial pressure was maintained higher than 60–65 mmHg and in all cases volume replacement was within published ranges (2,218.7 mL crystalloids, 5.6 units of PRBC and 857 mL FFP). Additionally, a TEG test was used to monitor coagulation and to guide the use of antifibrinolytic agents (fibrinogen/tranexamic acid) and platelet transfusions when indicated. These facts indicated that in our center the use of FFP and PRBC reached a similar level as reported by Zoltan G. Hevesi et al. (40) and was no longer used as the main volume expanders. Our results support in addition the notion that the utilization of TEG leads to a significant reduction in blood transfusion as previously reported (41).

During the operative phase maintenance of intraoperative normothermia is strongly recommended. Hypothermia is defined as core body temperature below 36 ℃. Intraoperative hypothermia leads to unfavorable outcomes for patients, such as delayed recovery from anesthesia and increased intraoperative blood loss (42). The latter might be due to ‘hypothermia-induced coagulopathy’, so called oozing (42), a condition in which a decrease in body temperature below 35 ℃ causes platelet dysfunction and body temperatures below 33 ℃ further disrupt the blood coagulation cascade (43). There are many factors that put patients at high risk of developing hypothermia during LTx operation. These include low operation room temperature, exposure of large area of internal organs, longer surgery time and utilization of large number of unwarmed fluids or blood products. Clinical significance of intraoperative hypothermia is less evaluated in LTx. Paterson et al. reported that intraoperative hypothermia during LTx might be an indicator of CMV infection within the 1st month postoperatively and active warming seems to reduce this risk (44). Eun Jung Oh et al. showed that patients without prewarming did not recover blood fibrinogen level even after 3 h after graft reperfusion (45). Therefore, we kept the operation room temperature at not less than 26 ℃, and the patient is covered appropriately and supplied with forced air warming (FAW) and body temperature monitoring is done every 30 minutes. Moreover, intravenous fluids of more than 500 mL are warmed to 37 ℃ in a temperature-controlled cabinet set between 38–40 ℃. Following these principles, we did not observe oozing in our patients.

Early endotracheal extubation is reported since the 1980’ies in cardiac and liver surgery (5,33). Improved technology in surgery and the utilization of faster elimination of anesthetic drugs shortens the duration of operation and patients to regain consciousness, which makes it possible to extubate early after LTx. LTx patients have a long course of disease or co-morbidities, and most of them have a poor basic physical condition; in addition, long duration of surgery and delayed correction of metabolic derangements may prevent early extubation. Physically, prolonged mechanical ventilation may increase right ventricular afterload and even induce venous congestion of the liver graft, while early extubation promotes spontaneously breathing could improve hepatic venous drainage, thereby facilitating early liver graft recovery and regeneration (46). Several studies have reported scoring systems to guide early endotracheal extubation following LTx in selected patients (46-48). The proposed criteria in these studies contain several variables, including the number of packed red cell transfusion, lactate at the end of surgery, duration of surgery, the use of vasoactive drugs at the end of surgery, the MELD score and hospital status of patients before LTx. These results have shown that in selected patients early extubation avoided the medical complications of prolonged ventilation and led to a shorter stay in ICU and significant cost saving (5). In our study, all patients were extubated within 6 hours in the ICU and then transferred to the IMC section stay. Mean total stay was 4.6 days. Our ERAS experience indicated that early extubation after LTx was safe and feasible. Postoperative pleural effusions, atelectasis and infections are common pulmonary complication following LTx (28). LTx patients with pleural effusions are associated with longer hospital length of stay and higher tracheostomy rates (49). Previously, it has been reported that severe pleural effusion may increase the incidence of lung infection in LTx (50) and recipients with pleural effusions had a higher rate of tracheostomy (49). Therefore, we performed a routine CT scan of the lung and sputum culture was routinely taken to rule out pulmonary complications; in addition, we initiated postoperative respiratory exercise and rehabilitation in ICU/IMC and general ward. The target exercise and respiratory frequency was 30 minutes every 2–3 hours and 10 minutes per hour, respectively. In addition, we performed BAL in case of left lower lobe atelectasis, increased white blood cell (WBC) and/or fever. We noticed that the early respiratory and exercise rehabilitation resolved the atelectasis and facilitated reduction in pleural effusions. In our center, only five patients needed pleural drainage due to effusion, but none of our patient’s experienced pneumonia or the need for reintubation or tracheostomy. Our data indicate that a preemptive strategy as described fosters early rehabilitation for liver-transplant recipients, is safe, tolerable, feasible and supported functional outcomes.

Prolonged nasogastric intubation in abdominal surgery is associated with increased pulmonary complications and longer time to return of bowel function. Therefore, it is recommended that prophylactic nasogastric intubation should be abandoned in favor of selective use in abdominal surgery (51,52). A systematic review shows that early enteral nutrition may contribute to better immune function and lower rates of infectious complications (53). Currently, there is lack of consensual evidence related to nasogastric intubation in LTx patients. It is strongly recommended that normal food oral intake should be started 12–24 h after LTx, according to the patient’s tolerance (9). In our study, we successfully removed the nasogastric tube within 48 hours after LTx and started oral intake training according to our SOP (Table 3) in order to facilitate bowel movement, reducing the time of flatus and the possibility of postoperative ileus, without any problems.

Prevention of thrombosis and bleeding complications are critical in postoperative management of LTx patients. Thromboprophylaxis is recommended in recipients at risk of hepatic artery and portal venous thrombosis, for example occlusive portal vein thrombosis (PVT) prior to LTx, complex physiological anastomosis, technical difficulties or non-physiological anastomosis (54). Preoperative evaluation of recipients and comprehensive communication with anesthetist and surgeon are necessary. We did not anticoagulated our patients instead stressed for fast ambulation after extubation. One patient developed a deep vein thrombosis on POD 25 and was put on anticoagulation.

Due to increased risk of bacterial, fungal, and viral infections of patients with end stage liver disease, postoperative prophylaxis of these pathogenic microorganism after transplantation is recommended. Hence, in our center, universal antibiotic prophylaxis of bacterial infections was administrated for 4 days. Meanwhile, body temperature, cultures and drug sensitive tests of blood, sputum culture, abdominal drainage fluid are routinely performed in patients with risk of infection to guide the anti-bacterial therapy. Five patients had pleural effusion, treated with drainage and a CT was performed to rule out an atelectasis of the right lower lobe. In case of atelectasis, we choose BAL as early intervention including culture of samples (n=1). Cytomegalovirus (CMV) prophylaxis was administrated to recipients in case of DR+/R− constellations, no infections were observed. For recipients with HBV infection before LTx, HBV immune globin was intravenously administrated for 2 times every week for 5 weeks and entecavir was orally taken every day beginning at POD 1. Fungal infections are associated with immune deficiencies and immunosuppression and patients with liver transplants are at high risk of invasive fungal infections (IFIs). The mortality of IFIs in liver recipients ranges from 25% to 67% (55). MELD scores higher than 25, post-transplant acute kidney injury and pre-transplant fungal colonization seem to be potential risk factors for IFIs (56,57). Currently, using 1.3-beta D glucan (BDG) and galactomannan (GM) can be helpful in diagnosis of fungal infection, it remains challenging to distinguish between colonization and true infection. Therefore, diagnosis of fungal infection and antifungal prophylaxis should be given carefully and upon individual indication, and clinical manifestations. None of our patients suffered from a fungal infection.

Standardized and individualized immunosuppressive therapy is the key to guarantee the efficacy of transplantation (58). In principle, primary immunosuppression is started at the time of LTx to prevent any forms of rejection (58). Nevertheless, several studies have shown that complications related to overimmunosuppression, such as chronic kidney disease, de novo malignancies, diabetes, dyslipidemia and hypertension, compromised long-term patient survival rather than immunological graft loss (59-61). Therefore, achieving stable trough levels within a target range is important, particularly early after LTx. Here, we choose a well-developed concept already published with AR rates below 10% which was highly efficient (62-64). No acute rejections neither adverse effects were observed, and we followed a daily monitoring during the hospitalization phase. Moreover, did our patients stay within the aimed therapeutic range. In 28 patients with HCC, we switched from MMF to sirolimus. Only one patient demonstrated a very early recurrence, while the other patients at 1 year after transplantation demonstrated no recurrence. These data are in line with recent findings by Kang et al. (65), demonstrating that patients on minimized Tacrolimus and Everolimus had a significant better outcome compared to SOC (Standard of Care—Tac, MMF).

Conclusions

In conclusion, ERAS is feasible in LTx, consisting of preoperative, intraoperative and postoperative procedures. Comparison of outcome using benchmarks from the German quality assessment in liver transplantation (IQTIG reference) demonstrated excellent outcomes in terms of in-house mortality, LOS, 1-year patient survival and readmission rates, clearly indicating the benefit of an ERAS protocol to measure and improve quality management for patients. Our study revealed that ERAS in LTx can provide a safe management tool to monitor the patient throughout the whole hospital stay, providing quality service with low morbidities and absence of mortality throughout the observation period.

Acknowledgments

Funding: This work was supported by the Anhui Provincial Natural Science Foundation (No. 2108085MH256 to X.Y.) and the Fundamental Research Funds for the Central Universities (No. WK9110000055 to B.N., No. WK9110000131 to X.Y.).

Footnote

Reporting Checklist: The authors have completed the STROCSS reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-349/rc

Data Sharing Statement: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-349/dss

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-349/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-349/coif). B.N. serves as an unpaid editorial board member of HepatoBiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All transplantations and organ donations were approved by the hospital ethics committee of The First Affiliated Hospital of USTC and in accordance with the Declaration of Helsinki (as revised in 2013) and the Declaration of Istanbul. The study protocol was approved by the Ethics Committee of The First Affiliated Hospital of the USTC, within University of Science and Technology of China (2024-RE-107). Written informed consent of each patient was obtained before operation and for the publication of this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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