Brustia Raffaele

Slim Karem

Scatton Olivier
email: olivier.scatton@aphp.fr

Pr Olivier Scatton

ENHANCED RECOVERY AFTER HEPATIC SURGERY

Keywords: Chirurgie hépatique, hépatectomie, récupération améliorée après chirurgie, revue systématique Liver surgery, Hepatectomy, Enhanced recovery after surgery, systematic

Introduction:

In a majority of cases, enhanced recovery after surgery (ERAS) leads to a reduced rate of postoperative complications and shortened hospital stays following digestive surgery. The program's preoperative, perioperative and postoperative measures are implemented by the members of a motivated multidisciplinary team.

Having shown its merits in digestive surgery, ERAS would be particularly useful in hepatic surgery due to the elevated rates of morbidity and mortality this type of operation continues to entail.

The objective of this review was to evaluate the efficacy of ERAS in hepatic surgery.

Method:

This is a systematic narrative review of the literature on the efficacy of EAS in hepatic surgery by laparotomy or laparoscopy.

Results:

Notwithstanding a number of studies (n= 30 : 5 randomized trials, 14 cohort studies and 11 meta-analyses) less sizable than with regard to digestive surgery in general and colorectal surgery in particular, analysis of the literature confirms that in hepatic surgery, ERAS is associated with an overall decrease in complications by 30 to 60%, but without improvement in the rates of hospital readmission and postoperative mortality. All of the studies report a reduction in average length of stay (ALOS) by 2.3 days and in functional recovery, a more objective indicator than ALOS, by 2.5 days. As of now, the economic impact of the ERAS programs in hepatic surgery is neither positive nor negative, the abovementioned savings being counterbalanced by heightened costs for material and equipment.

Laparoscopic surgery is independently associated with better outcomes in terms of complications, functional recovery and ALOS; that is why it is important to incorporate this surgical approach in ERAS as often as possible. Given a lack of robust evidence, prehabilitation, which is a preoperative optimization process leading to improved functional reserve, has yet to be assigned a place in ERAS programs pertaining to hepatic surgery.

Possible roadblocks to application of an ERAS program can be overcome through coordination by a team leader, a motivated multidisciplinary team, training courses and dedicated teaching sessions.

Conclusion :

ERAS is a care improvement process that has a major play to play in organization of hepatic surgery, and its large-scale application is to be recommended.

KEY POINTS

1) The objective of ERAS is to decrease complication rates and to facilitate improved recovery. Its application in hepatic surgery is premised on a satisfactory level of evidence.

2) Implementation of an ERAS program in hepatic surgery is associated with a decrease in morbidity ranging from 30 to 60%, and with a readmission rate similar to what has been observed in conventional management.

3) Duration of hospital stay can be reduced by a mean 2.3 days, and functional recovery time by a mean 2.5 days. 4) Laparoscopy must be carried out whenever possible.

5) The rare published medico-economic studies have shown that ERAS in hepatic surgery has no significant impact on costs.

INTRODUCTION

The concept of Fast Track or Enhanced Recovery After Surgery (ERAS) was first introduced in the 1990s by H. Khelet and his colorectal surgery team, its objectives being to reduce the rate of postoperative complications and to shorten hospital stays [START_REF] Ljungqvist | Enhanced Recovery After Surgery: A Review[END_REF]. Wishing to achieve decreased response to surgical stress and improved recovery, the program is built around a coherent sequence of preoperative, peri-operative and postoperative measures based on scientific data in the literature. No single element is liable to improve surgical outcome; the key to success consists in synergy and in the sequencing of the phases of the program, one after another in the right order [START_REF] Ljungqvist | Enhanced Recovery After Surgery: A Review[END_REF][START_REF] Fearon | Enhanced recovery after surgery: a consensus review of clinical care for patients undergoing colonic resection[END_REF]. And if the program is to function effectively, with durably sound results, it behooves the multidisciplinary team working with a patient to possess complete and comprehensive vision of the care pathway and outcomes, with periodic readjustments brought on by regularly programmed audits [START_REF] Ljungqvist | Enhanced Recovery After Surgery: A Review[END_REF][START_REF] Fearon | Enhanced recovery after surgery: a consensus review of clinical care for patients undergoing colonic resection[END_REF].

For over 10 years and following publication of more than 580 studies, application of this type of program in digestive surgery has yielded a significant decrease in complication rates, more rapid functional recovery and less protracted hospital stays without heightened readmission rates [START_REF] Lau | Enhanced Recovery After Surgery Programs Improve Patient Outcomes and Recovery: A Meta-analysis[END_REF]. Some of the reasons for improved quality of care are: the introduction of mini-invasive surgical approaches, deeper understanding of surgical stress, and optimized anesthetic care [START_REF] Ljungqvist | Enhanced Recovery After Surgery: A Review[END_REF][START_REF] Fearon | Enhanced recovery after surgery: a consensus review of clinical care for patients undergoing colonic resection[END_REF][START_REF] Lau | Enhanced Recovery After Surgery Programs Improve Patient Outcomes and Recovery: A Meta-analysis[END_REF].

Since the publication of ERAS recommendations for colorectal surgery, dedicated protocols for pancreatic (2012), urological (2013), gastric (2014), major gynecological (2015) and bariatric surgery (2016) have followed [START_REF] Ljungqvist | Enhanced Recovery After Surgery: A Review[END_REF]. On the same token, several learned societies, including the French-speaking www.grace-asso.fr, have published recommendations specific to hepatic surgery; the main outlines are summarized in Table 1.

Wishing to achieve an overall synthetic vision of the results of ERAS in hepato-biliary surgery, we have carried out a systematic review of the literature.

METHOD

In accordance with the PRISMA recommendations (6), the PubMed and PubMed Central data bases have been interrogated with regard to all the studies carried out over the past 10 years (2008 -2018) with the following key words: "liver surgery" AND "ERAS" OR "enhanced recovery after surgery". Research activities carried out during February 2018 were updated in March 2018 (Flow chart, Figure I). Among the studies indexed (n=1009) subsequent to elimination of duplicates and studies deemed not relevant on the basis of the title and the abstract, 5 randomized studies, 14 cohort studies (results in Table II) and 11 meta-analyses (results in Table III) were included.

WHY ERAS IN HEPATIC SURGERY?

Notwithstanding improved surgical techniques, as well as laparoscopic approach and anesthetic care [START_REF] Egger | Anesthetic and operative considerations for laparoscopic liver resection[END_REF], hepatic surgery remains a major operation with mortality ranging from 3 to 5% and postoperative morbidity from 17 to 56%, particularly in patients suffering from sarcopenia and/or underlying hepatopathy [START_REF] Dokmak | Liver resections in the 21st century: we are far from zero mortality[END_REF].

Possible pulmonary, renal or septic complications [START_REF] Dokmak | Liver resections in the 21st century: we are far from zero mortality[END_REF][START_REF] Margonis | Prognostic impact of complications after resection of early stage hepatocellular carcinoma[END_REF], or hepatic insufficiency can lead to longer hospitalization, additional health care (medication, laboratory or imaging examinations, re-do surgery) and increased risk of mortality at 30 days (HR=2.96, 95% CI 1.07-8.17) [START_REF] Amini | Complication timing impacts 30-d mortality after hepatectomy[END_REF]. All of these consequences have a direct impact on health costs.

From an oncological standpoint, complications following hepatic surgery (metastases, hepatocellular carcinoma…) are associated with reduced overall and disease-free survival.

The activation of pro-inflammatory mediators responsible for impairment of immune response to cancer is one explanation for this phenomenon, as is delayed access to adjuvant treatment [START_REF] Margonis | Prognostic impact of complications after resection of early stage hepatocellular carcinoma[END_REF][START_REF] Matsuda | Does postoperative complication have a negative impact on long-term outcomes following hepatic resection for colorectal liver metastasis?: a meta-analysis[END_REF]. And yet, it is possible to implement and develop an ERAS program after this type of major surgery. The development of a laparoscopic approach, comprehension of the surgical stress associated with hepatic resection and optimized anesthetic care could help to minimize postoperative complications [START_REF] Ljungqvist | Enhanced Recovery After Surgery: A Review[END_REF].

As is the case in other surgical areas, while a decrease in general complications following application of an ERAS program is to be expected, this does not hold true for the complications "specific" to hepatic surgery.

THE PARTICULARITIES OF ERAS IN HEPATIC SURGERY

For each protocol -and the liver is no exception to the rule -there exists a common and constant base, represented by a number of generic elements throughout the care pathway [START_REF] Ljungqvist | Enhanced Recovery After Surgery: A Review[END_REF][START_REF] Abeles | Enhanced recovery after surgery: Current research insights and future direction[END_REF]:

-Preoperative (informative consultation, reduced preoperative fasting, antibiotic or antithrombotic prophylaxis, no anxiolytic premedication); -Peri-operative (short-acting anesthetic agents, suitable vascular filling, prevention of hypothermia, laparoscopic approach when medical expertise is available); -Postoperative (no gastric tube, systematic prevention of nausea and vomiting, early mobilization and refeeding, regularly programmed audits).

That much said, other elements have been added to the protocols dedicated to each specialty. Indeed, recommendations for ERAS in hepatic surgery have incorporated the following specific elements (4,5):

-Preoperative o Preoperative nutrition for undernourished patients. Malnutrition is a recognized reversible risk factor for complications in hepatic surgery. At-risk patients (weight loss >10-15%, severe malnutrition BMI <18.5Kg/m 2 , Albuminemia < 30 g/l) should be eligible for nutritional correction during the 7 days preceding surgery (which can be put off for 15 days) [START_REF] Weimann | ESPEN Guidelines on enteral nutrition: surgery including organ transplantation[END_REF].

o Proof of the efficacy of preoperative immuno-nutrition is presently weak. That said, a randomized controlled multicenter study on this topic -PROPILS (44) -was completed in June 2018, inclusions of 400 patients had been planned; the results are awaited with pronounced anticipation.

-Peri-operative o Preoperative steroids (30 mg/kg, 30 min -2 h before surgery). Administration of methylprednisolone can be carried out prior to hepatectomy on a healthy liver so as to reduce intraoperative stress, without increasing the risk of complications (45). This measure is nevertheless to be avoided in diabetics.

o Laparotomy: The choice of incision is left to the discretion of the surgeon. That said, it is preferable to avoid "mercedes" incision, which is associated with a higher rate of postoperative eventration than "J" (Makuuchi) incision and inverted "L"shaped incision [START_REF] D'angelica | Optimal abdominal incision for partial hepatectomy: increased late complications with Mercedes-type incisions compared to extended right subcostal incisions[END_REF].

o Laparoscopy: The second international consensus conference on laparoscopic hepatic surgery [START_REF] Wakabayashi | Recommendations for laparoscopic liver resection: a report from the second international consensus conference held in Morioka[END_REF] concluded that for minor resections, laparoscopic approach is now standardized, and that it is associated with less blood loss, shorter hospital stay and fewer complications. Major resections by laparoscopy are not yet considered as standard, and remain limited to expert centers. o Postoperative drainage. Absence of prophylactic drainage after hepatectomy is not associated with increased risk of complications [START_REF] Wong-Lun-Hing | Abandoning Prophylactic Abdominal Drainage after Hepatic Surgery: 10 Years of No-Drain Policy in an Enhanced Recovery after Surgery Environment[END_REF]. However, given the low level of evidence, no learned society has put forward recommendations for or against drainage.

o Prevention of gastric emptying disorders. In cases of hepatectomy or left lobectomy, gastric emptying disorders, which result from contact of the sectioned edge with the stomach, could be minimized by interposing a greater omentum flap.

-Postoperative o Epidural analgesia is not more advantageous, in terms of attenuated inflammatory response or lessened pain, than multimodal anesthesia including, among other anesthetics, analgesia by cicatricial catheter [START_REF] Bell | Epidural versus local anaesthetic infiltration via wound catheters in open liver resection: a meta-analysis[END_REF].

o Peri-operative and postoperative blood glucose surveillance. Due to the transitory resistance to insulin induced by surgical stress, hyperglycemia is frequently noted.

As a result, insulin treatment must be initiated at an early phase of the hepatectomy so as to maintain normoglycemia (80-120 mg / dL). Preoperative oral carbohydrate supplementation seems to reduce resistance to insulin following hepatectomy (4).

Use of generic elements as a "hard core" to be supplemented and enriched by specific elements allows for elaboration of a fully complete ERAS protocol likely to dynamically evolve as scientific knowledge advances.

THE RESULTS OF ERAS IN HEPATIC SURGERY

Improved postoperative recovery is, by definition, central to ERAS programs. In order for its efficacy to be assessed, recovery must be measured as objectively as possible by means of one or more indicators. In this review we shall focus on different indicators or primary endpoints such as morbidity, mortality, average length of hospital stay (ALOS) and the economic repercussions of ERS programs.

MORBIDITY

Sound data confirm that complications following hepatic surgery have a negative impact on short-term and long-term survival [START_REF] Margonis | Prognostic impact of complications after resection of early stage hepatocellular carcinoma[END_REF][START_REF] Matsuda | Does postoperative complication have a negative impact on long-term outcomes following hepatic resection for colorectal liver metastasis?: a meta-analysis[END_REF].

The objective of the ERAS programs is to decrease complications by reducing response to surgical stress (1-3).

In the different published studies on hepatic surgery (Table II), given the low patient population, decrease in complications is not necessarily always significant [START_REF] Van Dam | Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection[END_REF][START_REF] Stoot | The effect of a multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study[END_REF][START_REF] Sánchez-Pérez | Fast-track program in laparoscopic liver surgery: Theory or fact?[END_REF][START_REF] Schultz | Evaluation of a fast-track programme for patients undergoing liver resection[END_REF][START_REF] Jones | Randomized clinical trial on enhanced recovery versus standard care following open liver resection[END_REF][START_REF] Dunne | Enhanced recovery in the resection of colorectal liver metastases[END_REF][START_REF] Dasari | Safety and feasibility of an enhanced recovery pathway after a liver resection: prospective cohort study[END_REF][START_REF] He | The effect of enhanced recovery program for patients undergoing partial laparoscopic hepatectomy of liver cancer[END_REF][START_REF] Savikko | Enhanced recovery protocol after liver resection[END_REF][START_REF] Hughes | Short-term outcomes after liver resection for malignant and benign disease in the age of ERAS[END_REF][START_REF] Joliat | Cost-Benefit Analysis of the Implementation of an Enhanced Recovery Program in Liver Surgery[END_REF][START_REF] Liang | Enhanced Recovery Program Versus Traditional Care in Laparoscopic Hepatectomy[END_REF][START_REF] Page | Patient outcomes and provider perceptions following implementation of a standardized perioperative care pathway for open liver resection[END_REF][START_REF] Ratti | Impact of ERAS approach and minimally-invasive techniques on outcome of patients undergoing liver surgery for hepatocellular carcinoma[END_REF][START_REF] Kaibori | Effects of implementing an "enhanced recovery after surgery" program on patients undergoing resection of hepatocellular carcinoma[END_REF][START_REF] Wong-Lun-Hing | Randomized clinical trial of open versus laparoscopic left lateral hepatic sectionectomy within an enhanced recovery after surgery programme (ORANGE II study)[END_REF][START_REF] Fretland | Laparoscopic Versus Open Resection for Colorectal Liver Metastases: The OSLO-COMET Randomized Controlled Trial[END_REF][START_REF] Ovaere | The Effectiveness of a Clinical Pathway in Liver Surgery: a Case-Control Study[END_REF][START_REF] Tufo | Hepatectomy for octogenarians with colorectal liver metastasis in the era of enhanced recovery[END_REF].

However, when focusing on the nine most recent studies (2016-2018), including two randomized trials, we have observed a significant decrease in complications in the ERAS group (1%-49%) versus control group (10%-64%) (17-25) (Table II).

A meta-analysis dealing with the impact of ERAS following non-colorectal (bariatric, hepatic, pancreatic, esophago-gastric, uro-gynecological) surgery in 6511 patients (3456 ERAS vs 3055 control) highlighted a 30% decrease in complications in the ERAS group (OR 0.70, 95% CI: 0.56-0.86, P = 0.001) [START_REF] Visioni | Enhanced Recovery After Surgery for Noncolorectal Surgery?: A Systematic Review and Meta-analysis of Major Abdominal Surgery[END_REF].

These results are in agreement with those of 11 more selective meta-analyses [START_REF] Lei | Fast-track programs versus traditional care in hepatectomy: a meta-analysis of randomized controlled trials[END_REF][START_REF] Hughes | Enhanced recovery following liver surgery: a systematic review and meta-analysis[END_REF][START_REF] Ni | Enhanced recovery after surgery programs in patients undergoing hepatectomy: A meta-analysis[END_REF][START_REF] Wu | Fast-Track Programs for Liver Surgery: A Meta-Analysis[END_REF][START_REF] Yang | Enhanced recovery after surgery programs versus traditional perioperative care in laparoscopic hepatectomy: A meta-analysis[END_REF][START_REF] Song | The enhanced recovery after surgery (ERAS) program in liver surgery: a meta-analysis of randomized controlled trials[END_REF][START_REF] Ahmed | Fast track program in liver resection: a PRISMA-compliant systematic review and meta-analysis[END_REF][START_REF] Li | Fast track for open hepatectomy: A systemic review and meta-analysis[END_REF][START_REF] Li | Enhanced recovery program versus traditional care after hepatectomy: A meta-analysis[END_REF][START_REF] Zhao | Enhanced recovery after surgery program reduces length of hospital stay and complications in liver resection: A PRISMA-compliant systematic review and meta-analysis of randomized controlled trials[END_REF][START_REF] Wang | Enhanced Recovery after Surgery Programs for Liver Resection: a Meta-analysis[END_REF] on the impact of ERAS in hepatic surgery in a number of patients ranging from 372 to 2575; once again, a significant decrease in complications in the ERAS group (0.34<OR<0.94) (Table III) appear.

However, when these different results are observed in detail, they are not homogeneous. While all of the meta-analyses under consideration [START_REF] Lei | Fast-track programs versus traditional care in hepatectomy: a meta-analysis of randomized controlled trials[END_REF][START_REF] Hughes | Enhanced recovery following liver surgery: a systematic review and meta-analysis[END_REF][START_REF] Ni | Enhanced recovery after surgery programs in patients undergoing hepatectomy: A meta-analysis[END_REF][START_REF] Wu | Fast-Track Programs for Liver Surgery: A Meta-Analysis[END_REF][START_REF] Yang | Enhanced recovery after surgery programs versus traditional perioperative care in laparoscopic hepatectomy: A meta-analysis[END_REF][START_REF] Song | The enhanced recovery after surgery (ERAS) program in liver surgery: a meta-analysis of randomized controlled trials[END_REF][START_REF] Ahmed | Fast track program in liver resection: a PRISMA-compliant systematic review and meta-analysis[END_REF][START_REF] Li | Fast track for open hepatectomy: A systemic review and meta-analysis[END_REF][START_REF] Li | Enhanced recovery program versus traditional care after hepatectomy: A meta-analysis[END_REF][START_REF] Zhao | Enhanced recovery after surgery program reduces length of hospital stay and complications in liver resection: A PRISMA-compliant systematic review and meta-analysis of randomized controlled trials[END_REF][START_REF] Wang | Enhanced Recovery after Surgery Programs for Liver Resection: a Meta-analysis[END_REF] are in agreement as to a reduction in grade I complications (according to the Clavien-Dindo definition) in the ERAS group, only two of them report a reduction in more severe (Clavien-Dindo grades II-IV or II-V) complications) [START_REF] Yang | Enhanced recovery after surgery programs versus traditional perioperative care in laparoscopic hepatectomy: A meta-analysis[END_REF][START_REF] Li | Enhanced recovery program versus traditional care after hepatectomy: A meta-analysis[END_REF]. Moreover, the results of these two meta-analyses should be considered with caution given (a) variable definitions of severe complications and (b) the almost exclusively Asian authorship of the studies included, a possible source of bias.

The hypotheses possibly explaining this heterogeneity are based on (a) varied selection criteria (illness severity, resection indications, surgical approach, extension of resection); (b) varied compliance (within a center or between centers) with items in the ERAS protocol and;

(c) varied appraisals of morbidity.

To conclude, an overall decrease in complication rates in the ERAS programs is accompanied by similar readmission rates [START_REF] Song | The enhanced recovery after surgery (ERAS) program in liver surgery: a meta-analysis of randomized controlled trials[END_REF][START_REF] Wang | Enhanced Recovery after Surgery Programs for Liver Resection: a Meta-analysis[END_REF], even when analyzing the sub-groups in randomized (OR = 2.10, 95% CI = 0.31-14.24, P = 0.45) and non-randomized (OR = 0.95, 95% CI = 0.66-1.36, P = 0.79) studies [START_REF] Wang | Enhanced Recovery after Surgery Programs for Liver Resection: a Meta-analysis[END_REF].

MORTALITY

There were no significant differences between the ERAS group and the control group in either the studies (7-11, 13-18, 22-25) or the meta-analyses [START_REF] Hughes | Enhanced recovery following liver surgery: a systematic review and meta-analysis[END_REF][START_REF] Wu | Fast-Track Programs for Liver Surgery: A Meta-Analysis[END_REF][START_REF] Song | The enhanced recovery after surgery (ERAS) program in liver surgery: a meta-analysis of randomized controlled trials[END_REF][START_REF] Ahmed | Fast track program in liver resection: a PRISMA-compliant systematic review and meta-analysis[END_REF][START_REF] Li | Fast track for open hepatectomy: A systemic review and meta-analysis[END_REF][START_REF] Wang | Enhanced Recovery after Surgery Programs for Liver Resection: a Meta-analysis[END_REF] (Tables II andIII). One of the explanatory hypotheses is that mortality subsequent to a hepatectomy remains a relatively rare event. What is more, in none of the studies was mortality considered as the primary endpoint; lastly, the size of a sample allowing a major difference in mortality to be underscored would be much greater than that of all the studies published up until now.

LENGTH OF HOSPITAL STAY

Length of hospital stay has long since been considered as an indirect marker of recovery and of health care system performance [START_REF] Maessen | Enhanced Recovery After Surgery (ERAS) Group. Length of stay: an inappropriate readout of the success of enhanced recovery programs[END_REF].

Generally speaking, ERAS in hepatobiliary surgery is associated with pronouncedly shortened hospital stay. A recent European case-control study compared ERAS versus standard care pathways in hepatobiliary surgery in 100 patients (n=50 ERAS, n=50 control) who were matched with regard to extent of resection, tumor location and open/laparoscopic surgical approach. In the ERAS group, a reduction of 38% (2.5 days) in length of hospital stay (4 days ERAS group vs 6.5 days control group, p < 0.001) was observed, but there was no significant difference in terms of postoperative complication or hospital readmission rate [START_REF] Ovaere | The Effectiveness of a Clinical Pathway in Liver Surgery: a Case-Control Study[END_REF].

The meta-analyses in hepatic surgery taking this type of indicator into consideration reported a mean reduction in length of hospital stay of 2.07 to 3.31 days in the ERAS group (26-36) (Table III).

Using these data, we may summarize by concluding that application of an ERAS program in hepatic surgery brings about a mean reduction in length of hospital stay (duration) of 2.3 days (Table II). However, non-medical logistics-related factors can also determine length of hospital stay and, in some cases, delay a patient's return home. Some of the most common factors are: absence of a family network or home help services, incompatibility between the theoretical date of discharge and its organizational feasibility (no discharge over the weekend, no medical products available at the town pharmacy, etc.) [START_REF] Abeles | Enhanced recovery after surgery: Current research insights and future direction[END_REF]. Moreover, in some cases a patient may fulfill the existing discharge criteria but experience "cultural" anxiety regarding a return home considered as premature [START_REF] Abeles | Enhanced recovery after surgery: Current research insights and future direction[END_REF][START_REF] Maessen | Enhanced Recovery After Surgery (ERAS) Group. Length of stay: an inappropriate readout of the success of enhanced recovery programs[END_REF]. The time interval between a patient's surgical intervention and that person's functional recovery seems to be a more objective parameter than length of hospital stay, especially insofar as logistical constraints may vary between one center or country and the next. From a medical standpoint, authorization for discharge (on medical indication) is justified when the listed consensual criteria for functional recovery (52, 53) have been fulfilled.

FUNCTIONAL RECOVERY

Two studies that have considered functional recovery time as an evaluation criterion report different results. A first cohort study of 184 patients comparing the periods before and after initiation of an ERAS strategy failed to show differences in either functional recovery time (5 vs 5 days, NS), or length of hospital stay (6 vs 6 days, NS) [START_REF] Dasari | Safety and feasibility of an enhanced recovery pathway after a liver resection: prospective cohort study[END_REF]. By contrast, a second randomized controlled study of 91 patients comparing an ERAS program to a control group with a standard program showed a 50% reduction in functional recovery time (3 vs 6 days, p<0.001) [START_REF] Jones | Randomized clinical trial on enhanced recovery versus standard care following open liver resection[END_REF].

While the first study [START_REF] Dasari | Safety and feasibility of an enhanced recovery pathway after a liver resection: prospective cohort study[END_REF] did not specify the list of criteria for authorized discharge, the second study [START_REF] Jones | Randomized clinical trial on enhanced recovery versus standard care following open liver resection[END_REF] applied the following criteria: 1) good tolerance of oral nutrition; 2) good pain control by oral analgesics; 3) independent mobilization; 4) normal or improving bilirubin levels; 5) the patient's wish for discharge from hospital.

The two meta-analyses employing this indicator reported a relative difference in mean functional recovery time of -2.30 days, (95% CI -3.77 -0.83; p = 0.002) (31) and -2.67 days (95% CI -3.68 -1.66; p<0.00001) [START_REF] Li | Enhanced recovery program versus traditional care after hepatectomy: A meta-analysis[END_REF] in favor of the ERAS group. "Supplementary" hospitalization time is defined as the difference between functional recovery time and actual length of hospital stay. In the Orange II trial (left lobectomy: laparoscopic vs. open surgery), it averaged 20 to 40%, and was attributed to logistical reasons in 38 to 46% of cases, and to medical reasons in 8 to 15% [START_REF] Wong-Lun-Hing | Randomized clinical trial of open versus laparoscopic left lateral hepatic sectionectomy within an enhanced recovery after surgery programme (ORANGE II study)[END_REF].

ECONOMIC IMPACT

ERAS programs often bring about health care savings in digestive surgery [START_REF] Lee | A systematic review of economic evaluations of enhanced recovery pathways for colorectal surgery[END_REF], which may be explained by less time spent in ICUs, reduced consumption during medical treatments (drainages, intravenous therapies, etc.) and a lessened need for biological and imagerybased examinations [START_REF] Joliat | Cost-Benefit Analysis of the Implementation of an Enhanced Recovery Program in Liver Surgery[END_REF], which may be associated with a lower rate of complications and/or standardized care pathways [START_REF] Joliat | Cost-Benefit Analysis of the Implementation of an Enhanced Recovery Program in Liver Surgery[END_REF].

In hepatobiliary surgery, on the other hand, up until now ERAS has shown no significant impact on the aforementioned medico-economic aspects.

A study carried out in the United States focusing on reduction of unnecessary expenses and wasted resources demonstrated that ERAS implementation in hepatic surgery was associated with a 41% decrease of the additional costs inherent to laboratory examinations and a 22% diminution of expenses related to medical treatment [START_REF] Page | Patient outcomes and provider perceptions following implementation of a standardized perioperative care pathway for open liver resection[END_REF]. However, two recent European studies failed to observe any overall economic effect [START_REF] Joliat | Cost-Benefit Analysis of the Implementation of an Enhanced Recovery Program in Liver Surgery[END_REF][START_REF] Ovaere | The Effectiveness of a Clinical Pathway in Liver Surgery: a Case-Control Study[END_REF]. Detailed analysis paradoxically showed an increase in costs incurred during the intraoperative period, the augmentation being due to a heightened percentage of operations performed by laparoscopy [START_REF] Joliat | Cost-Benefit Analysis of the Implementation of an Enhanced Recovery Program in Liver Surgery[END_REF][START_REF] Ovaere | The Effectiveness of a Clinical Pathway in Liver Surgery: a Case-Control Study[END_REF] and to use of an ultrasound dissector (Cavitron Ultra Sound Aspirator: CUSA) (24) in the ERAS group. Cost reduction during the postoperative period in the ERAS group may be attributed to shortened hospital stays and lessened complications; so it is that the balance sheet was at the "break-even point", notwithstanding the expenses necessarily entailed by ERAS implementation.

One must not forget that whether in the operating theater or in intensive care, length of hospital stay is strongly contingent on the habits prevailing in different centers and countries. That is why the most relevant indicator is not absolute difference, but rather relative difference before vs. after implementation [START_REF] Joliat | Cost-Benefit Analysis of the Implementation of an Enhanced Recovery Program in Liver Surgery[END_REF].

Even though three meta-analyses pertaining to 580, 1400 and 2572 patients respectively reported a significant reduction of hospitalization costs [START_REF] Wu | Fast-Track Programs for Liver Surgery: A Meta-Analysis[END_REF][START_REF] Yang | Enhanced recovery after surgery programs versus traditional perioperative care in laparoscopic hepatectomy: A meta-analysis[END_REF][START_REF] Wang | Enhanced Recovery after Surgery Programs for Liver Resection: a Meta-analysis[END_REF] in the ERAS group, interpretation of these findings should take into account the geographical heterogeneity of the studies (Asia, Europe, the United States) and the inclusion of patients operated laparoscopically, a confounding factor for cost increase.

To sum up, only a small number of the randomized controlled studies on ERAS have dealt with the relevant economic data, and they are marked by pronounced methodological biases (53).

THE ROLE OF LAPAROSCOPY IN ERAS PROGRAMS

Taken alone, when compared with open surgery, mini-invasive surgery is associated with more rapid recovery, which is largely explained by reduced inflammatory response [START_REF] Fretland | Inflammatory Response After Laparoscopic Versus Open Resection of Colorectal Liver Metastases: Data From the Oslo-CoMet Trial[END_REF].

In digestive surgery, several studies have focused on the role of laparoscopy in an ERAS program. In a review of the literature, it was found that laparoscopically operated patient groups in an ERAS program had less lengthy hospital stays and lower rates of readmission at 30 days [START_REF] Abeles | Enhanced recovery after surgery: Current research insights and future direction[END_REF].

In hepatobiliary surgery, a study of the Orange II trial [START_REF] Wong-Lun-Hing | Randomized clinical trial of open versus laparoscopic left lateral hepatic sectionectomy within an enhanced recovery after surgery programme (ORANGE II study)[END_REF] comparing mini-invasive vs. open surgical approaches in left lobectomy and postulating functional recovery as the primary endpoint in an ERAS program was discontinued due to insufficient inclusion; on the one hand, the investigators noted that "keyhole" surgery was preferred in 74% of cases; on the other hand, before the end of the study the surgical community was convinced of the advantages of laparoscopy and did not wish to keep on randomizing the two types of approach.

A second randomized controlled trial involving 280 patients (the OSLO-COMET Trial) and comparing laparoscopic to open surgery in management of hepatic metastases in an ERAS program highlighted a 12% reduction in postoperative complications (95%IC : 1.67-21.8, p=0.021) in the mini-invasive group [START_REF] Fretland | Laparoscopic Versus Open Resection for Colorectal Liver Metastases: The OSLO-COMET Randomized Controlled Trial[END_REF]. It should be noted that in this superiority trial, comparison pertained not to the ERAS program, which was applied in the two arms of the trial, but rather to the chosen surgical approach (laparoscopy versus laparotomy).

A meta-analysis comparing ERAS versus standard management in hepatobiliary surgery showed a reduction in length of hospital stay in the sub-group of ERAS patients having undergone laparoscopy (WMD = -3.64, 95% CI = -4.63 to -2.64, P < 0.00001) as compared to an ERAS sub-group having undergone laparotomy (WMD = -1.79, 95% CI = -2.52 to-1 .06, P < 0. 00001) [START_REF] Wang | Enhanced Recovery after Surgery Programs for Liver Resection: a Meta-analysis[END_REF].

Independently of the specific weight of the ERAS program or of care pathway standardization, the observed benefits finally remain the same: better outcomes and improved recovery. That is why it matters to incorporate laparoscopy into ERAS to the greatest possible extent (17).

PRE-HABILITATION

Pre-habilitation represents a proactive process of preoperative optimization, which begins with disease diagnosis and continues up until an operation, the objective being to ameliorate functional reserves in the perspective of surgery [START_REF] Bolshinsky | Multimodal Prehabilitation Programs as a Bundle of Care in Gastrointestinal Cancer Surgery: A Systematic Review[END_REF][START_REF] Roy | The concept of prehabilitation: What the surgeon needs to know?[END_REF]. Known pre-habilitation measures include physical activity, nutritional support and/or immunonutrition, correction of anemia and psychological optimization. And as is the case with ERAS, when each of these interventions was tested alone (unimodal treatment), results were mixed.

Up until now, only one single blind randomized controlled trial in hepatic surgery testing the effect of 4 weeks of physical activity versus control on 35 patients (n=16 control group, n=19 experimental group) has reported improved cardiopulmonary resistance to effort in the prehabilitation arm. However, no difference was shown between the two groups in rate of postoperative complications or length of hospital stay [START_REF] Dunne | Randomized clinical trial of prehabilitation before planned liver resection[END_REF].

To conclude, up until now no study has been published on multimodal pre-habilitation in hepatic surgery. Moreover, the level of evidence derived from the studies in digestive surgery favorable to pre-habilitation remains at an early stage; sounder results are awaited before pre-habilitation measures are incorporated into ERAS programs.

OBSTACLES TO IMPLEMENTATION OF AN ERAS PROGRAM

Notwithstanding the high level of evidence of the ERAS programs, success of initiation, rate of compliance and speed of implementation can vary considerably from one center to the next. Some elements are simpler to put into practice than others, particularly when they are not far from daily routine; examples include prophylactic antibiotic treatment, thromboprophylaxis … and laparoscopic approach. Other elements are more difficult to put into practice, even when coaching has been carried out ; examples include absence of intraoperative drainage, early removal of urinary catheter, absence of opioids and "policy" of restrictive intraoperative vascular filling [START_REF] Abeles | Enhanced recovery after surgery: Current research insights and future direction[END_REF].

Frequently cited obstacles to ERAS program implementation include lack of nursing staff or financial resources, difficulties in communication or collaboration between team members, and natural averseness to change. Moreover, elements of the ERAS protocol with a low level of evidence are perceived as the most difficult, and those with a high level of evidence as the least difficult to incorporate [START_REF] Pearsall | A qualitative study to understand the barriers and enablers in implementing an enhanced recovery after surgery program[END_REF].

A meta-analysis of 11 studies in colorectal surgery has shown that out of 19 items in the ERAS protocol, only a mean number of 14 were actually used, and that they had little real impact on results [START_REF] Ahmed | Enhanced recovery after surgery protocols -compliance and variations in practice during routine colorectal surgery[END_REF]. In hepatobiliary surgery, there already exists a certain consensus with regard to elements such as a preoperative sweetened drink, absence of gastric catheter or systematic abdominal drainage, reduction of intraoperative infusions, refeeding and early mobilization, and early removal of urinary catheter [START_REF] Wang | Enhanced Recovery after Surgery Programs for Liver Resection: a Meta-analysis[END_REF].

The fact that compliance with the ERAS protocol has been one of the keys to its success is well-documented; for example, a French study on 1904 patients, 490 of whom had undergone colorectal surgery, showed that length of hospital stay was inversely proportional to the number of satisfactorily applied items of the ERAS program [START_REF] Veziant | Large-scale implementation of enhanced recovery programs after surgery. A francophone experience[END_REF].

Given the obstacles to implementation and the difficulty of determining the relative importance of each component of an ERAS protocol, it has been suggested that some degree of flexibility allowing for a personalized rather than a rigorously applied protocol could be proposed as a reflection of the wide-ranging variety of patients and procedures for whom and to which an ERAS program could be applied [START_REF] Lyon | Enhanced recovery programme in colorectal surgery: does one size fit all?[END_REF]. Factors facilitating its implementation could include special coordination by a team leader, a motivated multidisciplinary team, training courses and teaching sessions dedicated to the advantages of ERAS, and regularly planned audits [START_REF] Abeles | Enhanced recovery after surgery: Current research insights and future direction[END_REF][START_REF] Pearsall | A qualitative study to understand the barriers and enablers in implementing an enhanced recovery after surgery program[END_REF].

CONCLUSIONS

ERAS program implementation in hepatic surgery has been shown to be associated with a significant reduction in terms of postoperative complications, functional recovery time and length of hospital stay; on the other hand, it has failed to modify readmission rates. And while the laparoscopic approach can appreciably improve the results of this type of program, the level of evidence in favor of multimodal pre-habilitation in hepatobiliary surgery has remained low.

However, these conclusions should be modulated by the facts that (a) the available metaanalyses are based on a low number of randomized and cohort studies and (b) they are geographically heterogeneous (Europe, United States, China). In other words, in order to obtain a more precise perspective on the efficacy of ERAS in hepatic surgery, it will be necessary to carry out additional clinical studies.

Fig. 1

 1 Fig.1 Stratégie de recherche, sélection des études

Table I . Summary of the ERAS recommendations in hepatic surgery

 I

	17	Prevention of gastroparesia	Greater omentum flap on left hepatectomy surface.	High	High
	N 18 1 19 2 20 3 4 21 22 5 23	ELEMENT Stimulation of intestinal transit Preoperative consultation Early mobilization Preoperative nutrition Analgesia Systematic Immuno-nutrition Reduced prevention of postoperative nausea and vomiting. preoperative fast Vascular filling Oral bowel preparation Audit	SUMMARY No indication The patient should have a systematic dedicated consultation and targeted education before hepatectomy. Must be encouraged the day after the operation. No systematic indication of epidural anesthesia for open hepatectomies. An intrathecal infusion and a cicatricial At-risk patients (weight loss >10-15%, severe malnutrition BMI <18.5Kg/m2, Albuminemia < 30 g/l) should receive catheter are possible alternatives. nutritional correction 7 days before surgery (which can be put off for 15 days) Limited evidence Multimodal approach = intravenous administration of two anti-emetic molecules. Preoperative fast not exceeding 6h for solids and 2h for liquids. . Maintenance of central venous pressure <5cm H2O is Dedicated carbohydrate solution 2h before induction to be recommended, and balanced crystalloids are to be preferred to saline solutions or colloids. proposed. Bowel preparation is not indicated Regularly programmed audits increase team adhesion and improve results.	LEVEL OF EVIDENCE High Moderate Low Moderate High Low Moderate Moderate Low Moderate Low Moderate	DEGREE OF High RECOMMENDATION Low High High High Low High High High Low Low High
		No anxiolytic pre-	Long-acting anxiolytic premedication is to be avoided.
	6	medication	Anxiolytics with short half-life are to be preferred to	Moderate	High
			anesthetic induction.
			Low-molecular-weight heparin, 2-12h before surgery	Moderate	High
	7	Antithrombotic prophylaxis
			Intermittent pneumatic compression of the lower limbs during hepatectomy.	Low	Low
	8	Preoperative steroids	Metilprednysolone can be used before hepatectomy on increasing risk of complications. To be avoided in diabetics. healthy parenchyma to reduce intraoperative stress, without	Moderate	Low
			Intravenous antibiotic therapy 1h before incision (one dose).
		Antibiotic	Prophylactic postoperative antibiotic therapy not	Moderate	High
	9	prophylaxis and	recommended.
		skin preparation	Detersive skin cleaning with Chlorhexidine 2% superior to iodine solution.	Moderate	High
	10	Incision	No recommendations. Mercedes incision to be avoided (risk of eventration)	Moderate	High
	11	Mini-invasive approach	Laparoscopic surgery can be carried out by trained teams, segments. particularly left lobectomy or resections of anterior	Moderate	High
	12	Feeding tube (FT)	Systematic FT use increases the risk of pulmonary complications after hepatectomy.	High	High
		Systematic
	13	abdominal drainage	There exists no scientific proof for or against systematic abdominal drainage after hepatectomy.	Low	Low
	14	Prevention of hypothermia	Normothermia must be maintained during the hepatectomy.	Moderate	High
				Early refeeding = moderate	High
				Dietary
			A light meal (drink, dessert) is authorized from D1.	supplements =	Low
	15	Nutrition	Parenteral nutrition only in case of malnutrition or prolonged	moderate
			ileus (>5D)
				No systematic
				postoperative parenteral	High
				nutrition = high
	16	Postoperative glucose control	Insulin treatment to maintain normoglycemia	Moderate	High
					21

Table II -Cohort studies and randomized trials

 II RCT=randomized controlled trial, vs=versus Lap= laparoscopy, LLS=Left Lateral Sectionectomy/left lobectomy, y=years, *=statistically significant difference, S=Average length of stay, CRLM=colorectal liver metastasis, HCC=hepatocellular carcinoma ALOS=average length of stay, OR=Odds Ratio, RR=Relative Risk, MD=Mean Difference, WMD= Weighted Mean Difference, CI=Confidence Interval, dms = standardized difference

	3666.7€ control	Mortality (%) ALOS (days) recovery Cost effectiveness 1.5 vs 2.8 Functional 6 vs 6 Morbidity (%) (days) Mortality (%) Cost effectiveness	0 vs 2 * 6 vs 8 RR = 0.66, 95% CI 0.47-0.93; p = 0.02	0 5 vs 7 * 3 vs 5 25 vs 31 5 vs 7.5	0 2 vs 3 RR = 0.66, 95%CI 0.49-0.88; p = 0.005	0 RR = 0.65, 95% CI 0.52-0.81; p=0.0001 2 lap -5 ouverte RR=0.98, 95% CI 0.06-15.17; p=0.987 WMD=-0.45, 95% CI-0.78 -0.12; P=0.007	2 vs 2 * 4 vs 7 OR = 0.34, * 3 vs 6 WMD = 1.0, 95% CI 1.49 -	95% CI 0.15-0.75; p=0.008 0.51; p<0.0001	6 vs 6 RR = 0.98, RR = 0.67, 95 % CI 0.48-0.92; 95% CI 0.06-15.17; 1 vs 1 6 vs 6 p = 0.01 5 vs 5 p = 0.99	0 vs 0 * 6 vs 10 OR = 0.90, 95% CI 0.66-1.21; * 7742yen ERAS vs 9470yen control p=0.48 0 * 4 vs 6 RR = 0.94, 95% CI 0.79-1.12; 1.5 7 p=0.49 OR = 0.68, 95%CI 0.14 -3.34; p=0.64 RR = 0.63, 95% CI 0.19-2.15; p=0.46	1 vs 2 * 8 vs 10 OR = 0.45, 95% CI 0.30-0.67; 42,356€ ERAS vs 38,726€ control p < .0001 0 * 6 vs 10 OR = 0.52, 95% CI 0.37-0.72; * 5 vs 8	* 5 vs 6 p< 0.0001 OR = 0.65, 95% CI 0.50-0.84; Reduction of costs ERAS group OR = 0.81, 95% CI 0.31-2.12; p = 0.001 * 4 vs 6 * 3 vs 5 p = 0.67 SMD = -0.31, 95% CI -0.47 -0.14; p=0.0002	* 13 vs 16	0 lap * 4 lap 3 vs 3 vs 9 open vs 4.5 open	0 lap * 3.6 lap Same costs for the	vs 0.7 open vs 4.2 open groups	0 vs 0 * 4 vs 6.5 * 1912.2€ RAC vs	23
		Morbidity (%) * 20 vs 25.5 Functional recovery	(D)	31 vs 41	1 vs 1 3-5 vs 5-6.7	12 vs 12	25	15 vs 11			38 vs 38	WMD = -2.30, 95% CI	34 vs 33 -3.77 -0.83; p = 0.002	15 vs 16 MD = -2.09, 95% CI-	* 37 vs 71 3.32 -0.86; p=.0008	34	* 49 vs 64 WMD =2.67, 95% CI 3.68 -1.66; p<.00001	* 33 vs 44	* 1 vs 10	* 12-16 vs 26	19 vs 21	8 lap	vs 36 open	* 19 lap	vs 31 open	* 11 vs 32
	control	uthor Year Study Comparison Patients Lap/Open fo [25] 2018 cohort 80y 127 L-O Pt ERAS (D) ERAS 70y vs Year Comparison atients, Table III -Meta-analyses ERAS vs Dam [7] 2008 cohort control 161 O 372 WMD = -2.32, 95% CI -3.54 -1.11; p < 0.001 2014 ERAS vs control thor i [26]	oot [8] 2009 cohort ERAS vs control (Lap.) 26 L 838 2.5-7 vs 3-11 2014 ERAS vs control es [27]	nchez-2012 rez [9] cohort ERAS vs control 43 L 723 WMD = -2.77, 95% CI -3.87 -1.66; p < 0.00001 2015 ERA vs control [28]	ultz [10] 2012 cohort ERAS (descriptive) 100 L-O 1400 WMD = -2.25, 95% CI -3.10 -1.40; p<0.00001 2015 ERAS vs control [29]	nes [11] 2013 RCT ERAS vs control 91 L 580 MD = -3.31, 95%CI: -3.95 -2.67; 2016 ERAS vs control g [30]	nne [12] 2014 cohort initial vs delayed ERAS 304 L p<0.00001 WMD = -2.71, ERAS vs	sari [13] 2015 cohort ERAS vs control 184 L-O 634 95% CI -3.43 -1.99; p < 0.00001 2016 control g [31]	e [14] 2015 RCT ERAS vs control 86 L 810 MD =-2.74, 95% CI -3.60 -1.87; p<0.00001 ikko [15] 2015 cohort ERS vs control 134 L-O WMD = -2.24, 95% CI -hes [16] 2016 cohort ERAS (descriptive) 603 L-O 1027 3.69 -0.79; p< 0.005 WMD =2.72, liat [17] 2016 cohort ERAS vs control 174 L-O 524 95% CI 3.86 -1.57; p<.00001 ng [18] 2016 RCT ERAS vs control (Lap.) 187 L 996 ERAS vs ge [19] 2016 cohort control 117 O MD = -3.17, 95% CI -3.99 -2.35, p<0.001 2572 ERAS open WMD = -2.07, p < 0.00001 tti [20] 2016 cohort vs ERAS lap. vs 207 L-O 95% CI -2.76 -1.38; 2016 ERAS vs control 2016 ERAS vs control 2017 ERAS vs control 2017 ERAS vs control 2017 vs control ed [32] [33] [34] o [35] g [36] tients, control (HCC)	bori [21] 2017 cohort ERAS vs control (HCC) 71 O	ng-Lun-2017 ng [22] RCT ERAS open vs Lap (LLS) 24 L-O	land [23] 2018 RCT ERAS open vs Lap (CRLM) 280 L-O	ere [24] 2018 cohort ERAS vs 229 L-O