Enhanced recovery after surgery (ERAS) is a multimodal pathway developed to improve recovery after major surgery. Since its formal introduction in the 1990s, ERAS has been adopted quickly because of the cost efficiency derived from its reduction in length of hospital stays, an important issue in the context of current rapidly increasing healthcare costs and the consequent need for optimisation.1 2 Application of ERAS integrates various medical interventions involving surgeons, anaesthetists, physiotherapists, dieticians, and nurses.3 The benefits of ERAS have been well proven in colectomy.4 5 6 7 Liver cancer is the fourth leading cause of cancer death in both sexes worldwide.8 Liver resection remains the mainstay of curative treatment for liver cancer. Liver resection is associated with a high rate of postoperative morbidity ranging from 15% to 48%9 10 and a postoperative hospital stay of 9 to 15 days.11 The high rates of complications lead to prolonged hospital stay and increase costs of hospitalisation.

An ERAS programme combines a number of elements that aim to enhance postoperative recovery, facilitate earlier discharge, and reduce surgical stress response.3 4 It mainly focuses on minimising the impact of surgery on patient homeostasis.12 The reduction of postoperative physiological stress by attenuation of the neurohormonal response to the surgical intervention not only provides the basis for a faster recovery but also diminishes the risk of organ dysfunction and complications.13 Programmes for ERAS consist of well-organised pathways of clinical interventions that begin with out-patient preoperative information, counselling, and physical optimisation; proceed to pre-, intra-, and post-operative protocol-driven actions; and end with patient discharge following pre-established criteria.14 The main pillars of ERAS are extensive preoperative counselling, no bowel preparation, no sedative premedication, no preoperative fasting, preoperative carbohydrate loading, tailored anaesthesiology, perioperative intravenous fluid restriction, non-opioid pain management, no routine use of drains and nasogastric tubes, early removal of the urinary catheter, and early postoperative feeding and mobilisation.15 16 Several major studies have suggested that ERAS is feasible and significantly reduces complications and the length of hospital stay for patients undergoing colonic resection.4 5 6 7 17 Furthermore, ERAS has been successfully applied to urological,18 cardiovascular,19 gynaecological,20 orthopaedic,21 and thoracic surgeries.22 However, the literature on ERAS after liver resection is limited. The aim of the present study was to evaluate the safety and efficacy of an ERAS programme for open or laparoscopic liver resection.

This was a prospective feasibility study carried out in a tertiary academic hospital. The inclusion criteria recruited all consecutive patients undergoing elective liver resection who were aged 18 to 70 years, with American Society of Anesthesiologists (ASA) grade I or II, with no severe physical disabilities, who required no assistance with activities of daily living, and with informed consent available. Patients undergoing emergency surgery, who had received preoperative portal vein embolisation, who were expected to receive concomitant procedures other than cholecystectomy, who were mentally incapable of written consent, and women who were pregnant were excluded.

During the same period, 42 patients who fulfilled the same inclusion criteria underwent liver resection and a conventional perioperative programme, as the On-Q Pain Buster system (I-Flow Corporation, Lake Forest [CA], US) was not available for financial reasons. None of the control patients were assigned to that group because they refused the ERAS programme. Propensity score matching analysis was used to minimise bias and confounding factors in patient selection, and 20 matched pairs of patients were generated for comparison.

The same team of hepatobiliary surgeons experienced in both laparoscopic and liver surgery performed all operations. Our open and laparoscopic techniques have been described previously.23 In brief, open hepatectomy was performed via right subcostal incisions with upward midline extensions and in some cases with left subcostal extensions. In most cases, the liver was mobilised in standard fashion before parenchymal transection, whereas in the rest, we adopted the anterior approach or the hanging technique. Liver transection was performed with a cavitron ultrasonic surgical aspirator (Valleylab, Boulder [CO], US) and TissueLink (TissueLink Medical Inc, Dover [DE], US). For laparoscopic hepatectomy, a combination of TissueLink and LigaSure (Valleylab) were used for liver transection. The Pringle manoeuvre was not routinely applied during liver resection. Endovascular staplers (Tyco Healthcare, Norwalk [CT], US) were used to divide larger vascular pedicles.

Details of the ERAS programme and the conventional perioperative programme are summarised in Table 1. The design of the ERAS programme was based on consensus between our surgeons, anaesthetists, physiotherapists, dieticians and nurses, who reviewed the relevant literature and made appropriate adjustments to suit the local situation. Patients who were to undergo elective hepatectomy were first screened in an out-patient clinic or in wards for eligibility for the ERAS programme. Patients who fulfilled the inclusion and exclusion criteria were interviewed by the principal investigator or co-investigators for the recruitment and preoperative counselling. A guided tour on surgical ward led by a trained nurse and an information booklet about the preoperative guidance were given to each patient. The booklet described the method used for respiratory rehabilitation, daily medical events after admission, daily mobilisation goals, and nutritional goals after the operation. The patient was seen at a preoperative anaesthesia clinic for preoperative assessment of risk adjustment and education about the fast-track anaesthetic and postoperative pain management, especially during mobilisation.

All patients received a 20-mL local infiltration of local anaesthesia (0.25% levobupivacaine) followed by continuous wound instillation at 4 mL/h for 72 h using the On-Q Pain Buster System balloon pump (I-Flow Corporation). Pain control was supplemented using opioid-sparing multimodal analgesia, including oral paracetamol and non-steroidal anti-inflammatory drugs. For minimally invasive liver resection, continuous infiltration of the wound with local anaesthetic agents was used and early mobilisation started on postoperative day 0. The principal investigator held regular audit meetings with the research team and medical/nursing staff to ensure protocol compliance.

Patients could be discharged if they fulfilled the discharge criteria, which consisted of (1) adequate pain control with oral analgesics, (2) absence of nausea, (3) ability to tolerate solid food, (4) liver function on an improving trend, (5) mobilisation and self-support as compared to the preoperative level, and (6) acceptance of discharge by the patient.

The primary outcome of the study was total postoperative hospital stay, including that of patients readmitted within 30 days after surgery. The secondary outcomes of the study included the readmission rate and morbidity and mortality within 30 days.

The clinical outcomes of patients who underwent liver resection and received the ERAS programme were compared with those who received a conventional perioperative programme in the same period. Propensity score matching analysis was performed to control for potential bias. Sex, age, number of co-morbidities, ASA grade, diagnosis, presence of cirrhosis, and type of resection were chosen as our baseline covariates to calculate each patient’s propensity score. The propensity scores were estimated by fitting a logistic regression model with the above covariates. The patients were then matched by their propensity scores using one-to-one nearest neighbour matching without replacement.

Statistical analyses and propensity score matching calculations were performed using SPSS (Windows version 20.0; IBM Corp, Armonk [NY], US). Chi squared tests (or Fisher’s exact tests, when appropriate) were used to compare categorical data. Mann-Whitney U tests were used to compare continuous, non-normally distributed outcomes between treatment groups. A two-sided P<0.05 was considered to be statistically significant.

A total of 20 patients who underwent liver resection at Prince of Wales Hospital, Hong Kong, from September 2015 to July 2016, were recruited into the ERAS programme. Their median age was 58 years (range, 33-77 years). The majority (n=19, 95%) of the patients were in ASA grade II. Hepatocellular carcinoma (n=13, 65%) and colorectal liver metastasis (n=5, 25%) were the main indications for operation. All patients had Child-Pugh score class A. Major and minor hepatectomy were performed in eight (40%) and 12 (60%) patients, respectively. Minimally invasive hepatectomy (laparoscopic or robotic) were performed in nine patients, and the remaining 11 (55%) patients received open hepatectomy. There were no major complications as defined by the Clavien-Dindo classification of surgical complications, and no patients required readmission.24 25 Only two (10%) patients developed minor complications, which were wound seroma (n=1, 5%) and urinary retention (n=1, 5%).

The demographics of patients in the ERAS and conventional perioperative programme groups were comparable (Table 2). Perioperative outcomes are summarised in Table 3. There were no significant differences in patient demographics, liver function, tumour characteristics, or surgical techniques between the two groups. When compared with the conventional perioperative programme, the ERAS programme was associated with a significantly shorter postoperative hospital stay (5 vs 6 days, P=0.033). There was no significant difference in rates of postoperative complications or readmission.

Results from the present study indicate that the ERAS programme is safe and feasible in both open and laparoscopic liver resections in Hong Kong. There was a significant reduction in the length of postoperative hospital stay in the ERAS group.

Although ERAS programmes are not new, their development in liver resection has been relatively slow because of the operation’s high complexity and the high frequency of underlying liver cirrhosis in this group of patients. Patients with liver cirrhosis who undergo liver resection have special concerns that require special attention. Because the ERAS principles for liver resection were adapted from colonic surgery, more evidence is needed to prove the benefits of ERAS in liver resection and to tailor the elements of ERAS to liver resection.

For example, most ERAS programmes in open liver surgery use thoracic epidural analgesia. However, patients who undergo liver surgery experience transient coagulopathy after the operation, which may increase the risk of spinal hematoma if epidural analgesia is used. One previous study indicated that epidural analgesia increases the risk of bleeding and prolongs prothrombin time after liver resection.26 Furthermore, the majority of patients with liver cancer in our locality also had co-existing liver cirrhosis. This group of patients is coagulopathic even before liver resection, and the risk of bleeding complications related to the epidural analgesic is a particular concern.27 In the present study, we used an infusion pump for continuous infiltration of the wound with local anaesthetic agents for pain control in patients who underwent open liver resection. The acute pain service provided regular ward rounds to review pain control. Other analgesics would be added if pain control was unsatisfactory. We have previously studied the analgesic efficacy of this infusion pump in open liver surgery and found that total morphine consumption was reduced in patients who received continuous wound instillation of local anaesthetic after open liver surgery. This technique also effectively reduced pain at rest and after spirometry.28 The small size of the device can facilitate early mobilisation during the postoperative period. Recent recommendations of ERAS guidelines for liver surgery suggest that routine thoracic epidural analgesia is not recommended and that a wound infusion catheter is a good alternative.29

Restrictive use of surgical site drains after operation is one of the key elements of most ERAS protocols to support early mobilisation and reduce postoperative pain and discomfort.30 Recent meta-analyses did not recommend routine abdominal drainage in elective uncomplicated hepatectomy.31 However, cirrhotic patients are at risk of developing ascites and bleeding after liver resection. Therefore, according to the ERAS society recommendations for perioperative care for liver surgery, the available evidence is inconclusive, and no recommendation can be given either for or against the use of prophylactic drainage after hepatectomy.29 Data from larger studies are needed to evaluate the role of intra-abdominal drains in this specific group of patients.

Nevertheless, ERAS protocols might still be beneficial to cirrhotic patients, particularly in regard to the omission of overnight fasting and carbohydrate loading. Cirrhotic patients have decreased hepatic glycogen storage and impaired gluconeogenesis: an overnight fast is equivalent to a fast of 2 to 3 days in a healthy person. Omission of overnight fasting and carbohydrate loading may lessen the nutritional stress for these patients.

Shorter hospital stays have been reported after minimally invasive liver resection.23 32 33 Whether a similar decrease in hospital stay can be achieved by open surgery with an optimised fast-track programme remains unclear. In the current series, length of hospital stay was reduced by 1 day in both the minimally invasive and open surgery groups. However, only the difference in the open surgery group reached statistical significance. The major limitation of our study is its small sample size. Therefore, it did not have enough power to demonstrate statistical significance in small differences. Early reports on ERAS in liver surgery have demonstrated a significant reduction in hospital stay by 2 to 6 days.34 35 36 Some might contend that it was careful selection of patients that resulted in the reduction of length of stay. However, diverse groups publishing on consecutive series with ERAS principles have shown consistent results.30 It is highly likely that the ERAS protocol can shorten hospital stays. However, whether it can lead to a reduction in healthcare costs will be the focus of future studies in this field. Another limitation of this study is the uncertainty of balance of characteristics between the two groups. Standardised mean differences showed imbalances of some demographics (eg, body mass index and extent of hepatectomy) between the treatment groups, but the P values did not reach statistical significance. Again this is caused by the small sample size, which yields a model that is not sensitive enough to detect small differences.

The ERAS programme for liver resection is safe and feasible. It resulted in a reduction in hospital stay without an increase in morbidity and mortality. Larger-scale studies are needed to optimise the programme’s elements and study its cost-effectiveness.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Concept and design of study: CCN Chong, SKC Chan, PBS Lai.
Acquisition of data: WY Chung, YS Cheung, AKY Fung, AKW Fong, HT Lok.
Analysis or interpretation of data: CCN Chong.
Drafting of the article: CCN Chong.
Critical revision for important intellectual content: PBS Lai, SKC Chan, KF Lee, J Wong.

We would like to thank Mr Philip Ip for his statistical support in this project.

As an editor of the journal, PBS Lai was not involved in the peer review process. Other authors have no conflicts of interest to disclose.

The results of this project were presented in the 12th Biennial E-AHPBA Congress 2017 (23-26 May 2017, Mainz, Germany) and in the RCSEd/CSHK Conjoint Scientific Congress 2018 (15-16 September 2018, Hong Kong).

This project was supported by a Direct Grant from the Chinese University of Hong Kong (Ref No: MD14705).

The study was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (CREC 2015.024).

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