Jing-Jun He , Lei Geng , Zhuo-Yi Wng , Shu-Sen Zheng , , d, ∗
a Department of Infection Management, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310 0 03, China
b Division of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310 0 03, China
c Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310022, China
d NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310 0 03, China
End-stage liver disease (ESLD) usually causes multi-organ dysfunction which increases the risk for perioperative complications and mortality [1] . Liver transplantation is the only curative therapy for ESLD. However, liver transplantation is a major and challenging surgery with a great level of complexity as a result of the interaction between donor and recipient factors. Consequently,this procedure brings a high risk of complications that significantly affect 1-year mortality and graft loss [2] . In addition, immunosuppressant applications are required postoperatively. These factors make perioperative care of patients with liver disease complicated, and the risk of poor patient prognosis increases accordingly. Optimized perioperative management strategies benefit the patient rehabilitation and prolong survival. Enhanced recovery after surgery (ERAS) is a multimodal and evidence-based program of care to minimize the surgical stress, reduce perioperative morbidity and hospital stay [3] . ERAS strategies have been widely used in many fields for nearly 20 years, including colorectal, urological, orthopedics and other surgeries. However, as hepatic surgery differs significantly from colorectal or urological surgery in terms of underlying disease, comorbidities, metabolic stress response and organ-specific complications, the content of ERAS program for liver transplantation is specific. Although studies verified that ERAS is safe and effective in liver transplantation [ 4 , 5 ], it has not yet been widely accepted. This study summarized ERAS strategies of perioperative liver transplantation based on evidence-based medicine,and evaluated the effectiveness on clinical application.
The well-established routine ERAS strategies, such as shortening fasting time before surgery, unconventional enema and gastric tube intubation, reducing drainage tube placement during operation, and early postoperative oral intake, have been recognized.Liver transplantation, however, has its particularities compared with other operations, including preoperative education, intraoperative body temperature management, early cessation of mechanical ventilation, multimodal-balanced sedative and analgesia management, early physical activity, and nutritional support.
Adequate preoperative education is a key factor for the successful implementation of ERAS program. Currently, the health education of liver transplantation lacks multidisciplinary involvement,and nurse-led education method is a usual approach. However, the patient’s satisfaction and clinical outcome will be improved when a physician familiar with the patient’s condition is involved in the preoperative education. It is confirmed that patients could benefit from routine preoperative counseling and education before liver surgery. The health care providers can offer personalized, continuous and systematic health education through leaflets or multimedia information sources for patients to increase the involvement in decision-making process and also improve the compliance of medical care. In addition, patients are more aware of the procedure and details for postoperative tasks, and this may improve the results of perioperative feeding, mobilization and respiratory physiotherapy,thereby reducing complications after liver transplantation.
Effective intraoperative body temperature management is critical for postoperative rehabilitation. Hypothermia is defined as a core body temperature less than 36 °C. Intraoperative hypothermia increases the risk of intraoperative hemorrhage and the incision infection rate, as a result to prolong the length of hospital stay.Several active steps, such as raising the operating room temperature, using a heating blanket or heater, or heating the flushing liquid should be applied to prevent hypothermia. One study [6] certified that preheating the operating room for more than 25 min prior to anesthesia was an effective method to prevent intraoperative hypothermia. Hypothermia may also be improved during liver transplantation if the body temperature is regulated and kept over 36.5 °C before the portal vein is opened through various methods[7] .
Early extubation has become an important part of ERAS program for liver transplantation to minimize invasive approach. Several clinical studies have shown that the cessation of mechanical ventilation as soon as possible after the transplantation procedure reduces the incidence of ventilator-associated pneumonia and pleural effusion, and effectively shortens length of ICU stay and cuts down expenses [ 8 , 9 ]. This protocol helps the patients recover quickly after early extubation and allows them to be transferred to the surgical ward from the recovery room without ICU stay. In addition, this protocol is not associated with an increased rate of complications. Moreover, the protocol decreases the usage of intraoperative sedative drugs and anesthetic agents.
Effective postoperative analgesia is a prerequisite for the successful implementation of ERAS. Postoperative pain can be relieved safely and effectively by abandoning traditional analgesia instead of adopting a multimodal pain control scheme, such as patientcontrolled intravenous or intramuscular analgesia as well as sequential oral analgesia. Appropriate postoperative pain control not only reduces the risk of excessive sedation caused by drug overdose and the risk caused by prolonged postoperative mechanical ventilation, but also improves compliance of early physical activity. The American Pain Society strongly recommended using acetaminophen as the main component of postoperative multimodal analgesia after excluding contraindications [10] . Opiates are only regarded as the first-aid analgesics in consideration of the risk of respiratory depression for patients with liver dysfunction, and long-acting medication should be avoided [11] . Attention should be paid to adverse reactions during analgesia. For patients who have been medicated for more than one week, medication should be gradually stopped to prevent delirium. For the analgesia method,thoracic epidural analgesia is not suggested in liver transplantation for ERAS patients, while wound infusion catheter or intrathecal opiates can be good alternatives when combined with multimodal analgesia [12] .
Malnutrition is a crucial modifiable risk factor for adverse outcomes after liver transplantation in cirrhotic patients. The incidence of malnutrition caused by ESLD is 20%-50% [13] . A metaanalysis [14] of 7 randomized controlled trials containing 501 patients showed that perioperative nutrition management not only reduced the risk of infectious complications and improved incision healing for liver recipients, but also improved the function of the transplanted liver indicated by the reduced serum aspartate aminotransferase level. The European Society for Clinical Nutrition and Metabolism (ESPEN) suggests that patients with malnutrition or nutritional risks should receive nutritional treatment.Malnourished patients should receive 30-35 kcal/kg per day and a protein intake of 1.5 g/kg per day through a standard nutrition regimen in the preoperative period minimizing starvation period [15] .Furthermore, the intestinal function should be restored as soon as possible after transplantation. Enteral nutrition is an optimized nutrition method since it conforms to metabolic physiological characteristics, and maintains the structural and barrier functions of the intestinal mucosa. Refeeding syndrome must be avoided in nutritional treatment, and clinical practice should keep in mind that the nutrition support may increase the liver burden, even inducing hepatic encephalopathy possibly [16] .
Delayed gastric emptying (DGE) is another common complication at the same period of enteral nutrition after liver transplantation. DGE may prolong postoperative rehabilitation time and increase the economic burden of patients, therefore, early prevention is critical. Left-sided liver resection may be associated with a higher risk of DGE, which may relate with disruption of normal gastrointestinal movement at the point of contact between the stomach and cutting liver surface, and an omentum flap to cover cutting surface of the liver may be a method to reduce the risk of DGE after left-sided liver resection [17] . Also, a multimodal approach should be used to prevent postoperative nausea and vomiting.
Long-time bedridden is associated with multiple deleterious effects, such as muscle atrophy, thromboembolic disease and insulin resistance. Thus, early postoperative physical activity is important for patient rehabilitation. There is a traditional view that premature activity after operation may cause displacement of the transplanted liver and distortion of blood vessels. With improved surgical suture techniques and blood vessel anastomosis, moderate physical activity does not affect the function of transplanted liver;on the contrary, early mobilization is good for relieving postoperative fatigue, improving sleep quality, reducing complications and promoting rehabilitation. However, the safety of physical activity should always be the first-class priority considering the complexity of liver transplantation and the large size of incision. On this fundamental premise, the effect of exercise and patient compliance should be ensured maximumly. Although the safety of early mobilization has been confirmed, there is still lacking standard and systematic post-liver transplantation activity program in both traditional clinical practice and ERAS strategies. In particular, early mobilization completion rate and compliance are low. In addition,most patients and their caregivers considered that early physical activity increases the risk of wound pain, incision splitting and drainage tube slippage, which led to delayed or insufficient physical activity. Future research should focus on the development of physical exercise protocols after liver transplantation, which contain the frequency, intensity and duration, patient awareness and compliance on early postoperative activity.
ERAS has become a new strategy for perioperative management, while the safety and efficacy of ERAS strategies are particularly important according to the complexity of liver transplantation. At present, indictors like the length of hospital stay, incidence of postoperative complications and some surgical indexes are generally used to measure the effectiveness of ERAS. A prospective,single-blind randomized controlled study [18] revealed that ERAS strategies significantly shortened the duration of liver transplantation operation and the anhepatic period of the surgery, reduced intraoperative blood loss and blood transfusion rate, and shortened the ICU stays. A meta-analysis [19] indicated that ERAS reduced the incidence of total complications and transplant rejection rate,and improved patient satisfaction compared with the traditional group. Furthermore, systematic and goal-oriented ERAS rehabilitation management accelerated postoperative rehabilitation of patients with liver transplantation, reduced intraoperative red blood cell infusion and the postoperative tracheal reintubation rate, and improved the 90-day, 180-day and 1-year survival rates. Brustia et al. [20] found that ERAS shortened the length of hospital stay of liver transplantation recipients without increasing the incidence of complications and readmission. However, the terminal target of ERAS is to promote comprehensive rehabilitation of recipients including physical and mental function so that they can return to normal daily activities, rather than relieve symptoms temporarily.It takes more time for liver transplantation recipients to reintegrate into the society after hospitalization. Therefore, experts have suggested that mental health, post-discharge quality of life, incidence of late complications should also be included to improve the ERAS evaluation system.
Although ERAS Practice Guidelines for Gastric, Colorectal and Hepatic Surgery have been published, clinical practice should consider all possible obstacles when implementation of ERAS strategies, especially for liver transplantation. First, ERAS represents a paradigm shift in perioperative care by reevaluating traditional practices and modifying them based upon evidence-based practices. That means health care providers could be highly critical of this approach, even may refuse to comply with the ERAS guideline.Furthermore, clinical physicians and nurses’ lacking understanding of ERAS concept also affects ERAS im plementation. One cohort study [21] showed that the rehabilitation process of patients improved and the 5-year mortality rate reduced by 42% when more than 70% of ERAS strategies were implemented. Therefore, enhancing the ERAS knowledge of health care providers through training is the basis for ERAS implementation. Second, the complexity and uncertainty of ERAS implementation are intensified by liver transplantation patients’ poor preoperative state, which makes perioperative management much more difficult. Therefore, ERAS is not suitable for all patients. For example, ERAS strategies should be chosen cautiously for patients with acute liver failure or re-transplantation recipient. Third, patients’ viewpoint was another factor affecting clinical application of ERAS; for instance, patients thought ERAS program was fully dangerous influenced by traditional beliefs and culture.
In conclusion, ERAS is developed in a multimodal pathway to improve recovery after major surgery. The focus of ERAS strategies on liver transplantation has gradually shifted from early extubation, shorten the length of ICU stay and other single measures to multimodal holistic intervention. The existing studies usually had limited samples and short study period due to the shortage of donor liver. In addition, the majority of reports of successful application of ERAS always exclude patients with severe complications. Therefore, these conclusions should be carefully interpreted and applied in the clinical practice. Though the value of ERAS pathways has now been demonstrated, there is a need to perform highquality studies to confirm the benefit of ERAS protocols in liver transplantation.
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Jiang-Juan He: Data curation, Formal analysis, Writing - original draft. Lei Geng: Methodology, Writing - original draft. Zhuo-Yi Wang: Methodology, Writing - original draft. Shu-Sen Zheng: Conceptualization, Supervision, Writing - review & editing.
None.
Not needed.
No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.