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Enhanced recovery following liver surgery: a systematic review and meta-analysis

      Abstract

      Background

      Enhanced recovery after surgery (ERAS) programmes aim to improve postoperative outcomes. They are being utilized increasingly in hepatic surgery. This review aims to evaluate the impact of ERAS programmes on outcomes following liver surgery.

      Methods

      EMBASE, MEDLINE, PubMed and the Cochrane Database were searched for trials comparing outcomes in patients undergoing liver surgery utilizing ERAS principles with those in patients receiving conventional care. The primary outcome was occurrence of postoperative complications within 30 days. Secondary outcomes included length of stay (LoS), functional recovery and adherence to ERAS protocols.

      Results

      Nine articles were included in the review, of which two were randomized controlled trials (RCTs). Overall complication rates were 25.0% (range: 11.5–46.4%) in ERAS patients, and 31.0% (range: 11.8–46.2%) in conventional care patients. Significantly reduced overall complication rates following ERAS care were demonstrated by a meta-analysis of the data reported in the two RCTs (odds ratio: 0.49, 95% confidence interval 0.28–0.84; P = 0.01) The median LoS reported by the studies was 5.0 days (range: 2.5–7.0 days) in ERAS patients, and 7.5 days (range: 3.0–11.0 days) in non-ERAS patients. Recovery milestones, when reported, were improved following ERAS care.

      Conclusions

      The adoption of ERAS protocols improves morbidity and LoS following liver surgery. Future ERAS programmes should accommodate the unique requirements of liver surgery in order to optimize postoperative outcomes.

      Introduction

      Enhanced recovery after surgery (ERAS) programmes were introduced initially in colorectal surgery, in which they have been associated with improvements in postoperative length of stay (LoS) and morbidity.
      • Kehlet H.
      • Wilmore D.
      Evidence-based surgical care and the evolution of fast-track surgery.
      They have since been adopted by multiple specialties, including orthopaedic surgery,
      • Scott N.
      • McDonald D.
      • Campbell J.
      • Smith R.
      • Carey A.
      • Johnston I.
      • et al.
      The use of enhanced recovery after surgery (ERAS) principles in Scottish orthopaedic units – an implementation and follow-up at 1 year, 2010–2011: a report from the Muculoskeletal Audit, Scotland.
      gynaecology
      • Lv D.
      • Wang X.
      • Shi G.
      Perioperative enhanced recovery programmes for gynaecological cancer patients.
      and breast surgery.
      • Arsalani-Zadaeh R.
      • ElFadl D.
      • Yassin N.
      • MacFie J.
      Evidence-based review of enhancing postoperative recovery after breast surgery.
      The underlying principle of ERAS is a multimodal perioperative protocol to attenuate the inflammatory response and potentiate patient rehabilitation following major surgery.
      • Kehlet H.
      Multimodal approach to control postoperative pathophysiology and rehabilitation.
      The intention is to prevent the problems associated with an exaggerated inflammatory reaction to surgery, such as poor healing, infective complications and organ dysfunction.
      • Holte K.
      • Kehlet H.
      Epidural anaesthesia and analgesia – effects on surgical stress response and implications for postoperative nutrition.
      This approach, incorporating intensive optimization of mobility, gut function and analgesia,
      • Grade M.
      • Quintel M.
      • Ghadimi M.
      Standard perioperative management in gastrointestinal surgery.
      contributes to expediting recovery and minimizing morbidity.
      Enhanced recovery after surgery programmes reduce postoperative morbidity rates following a variety of surgical procedures.
      • Kehlet H.
      • Wilmore D.
      Evidence-based surgical care and the evolution of fast-track surgery.
      Liver resections have traditionally been associated with high mortality and morbidity rates. With current surgical and perioperative management, mortality rates of <5% can be achieved.
      • Palavecino M.
      • Kishi Y.
      • Chun Y.
      • Brown D.
      • Gottumukkala V.
      • Lichtiger B.
      • et al.
      Two-surgeon technique of parenchymal transection contributes to reduced transfusion rate in patients undergoing major hepatectomy: analysis of 1557 consecutive liver resections.
      However, morbidity rates remain high at 15–50%.
      • Virani S.
      • Michaelson J.
      • Hutter M.
      • Lancaster R.
      • Washaw A.
      • Henderson W.
      • et al.
      Morbidity and mortality after liver resections: results of the patient safety in surgery study.
      Adopting ERAS protocols may facilitate further improvement in surgical outcomes in hepatic resection.
      Recently, a number of publications have examined the application of ERAS programmes to hepatic surgery. This review evaluates the impacts of these programmes on morbidity and recovery rates following liver surgery.

      Materials and methods

      This study was conducted according to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines for meta-analysis.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      A literature search of EMBASE, MEDLINE, PubMed and the Cochrane Database was performed independently by two researchers in May 2013.
      The databases were searched for the period 1966–2013 using the key terms ‘enhanced recovery’, ‘fast track’, ‘ERAS’ and ‘liver’, ‘hepatobiliary’, ‘hpb’. All abstracts were reviewed for relevance. The full texts of relevant articles were subsequently reviewed.
      All trials assessing enhanced recovery following liver surgery were included. Inclusion criteria required that the study should clearly state the ERAS protocol, which should contain at least four items of care considered to be contributory to an enhanced recovery programme.
      • Coolsen M.
      • Wong-Lun-Hing E.
      • van Dam R.
      • van der Wilt A.
      • Slim K.
      • Lassen K.
      • et al.
      A systematic review of outcomes in patients undergoing liver surgery in an enhanced recovery after surgery pathways.
      Exclusion criteria discounted any studies involving children aged 16 years and younger, and any studies that reported the use of a non-standard care pathway or compared ERAS protocols in both arms of the study.
      All studies included in the final analysis were assessed by two independent reviewers. Study quality and bias were assessed independently using the Downs and Black score.
      • Downs S.
      • Black N.
      The feasibility of creating a checklist for the assessment of the methodological quality both of randomized and non-randomized studies of health care interventions.
      Data were extracted directly from the papers according to data extraction forms.
      The primary outcome was the occurrence of any complication within 30 days postoperatively. The following markers were assessed as secondary outcomes: LoS; time to the achievement of functional recovery; time to independent mobility; time to resumption of diet, and time until first bowel motion/flatus.
      The meta-analysis was performed using RevMan Version 5.2 (Nordic Cochrane Centre, Copenhagen, Denmark). Dichotomous data were analysed using the fixed-effects odds ratio. Heterogeneity was assessed using I2 and chi-squared tests and judged to be significant if the I2-value was >50% and according to a P-value of <0.05. The cut-off for statistical significance was set at P < 0.05. When continuous quantitative data were not distributed normally, meta-analysis was not performed and a qualitative assessment was utilized.

      Results

      Study characteristics

      A total of 257 papers were identified. The PRISMA diagram is shown in Fig. 1. Nine studies were included for review.
      • van Dam R.
      • Hendry P.
      • Coolsen M.
      • Bemelmans H.
      • Lassen K.
      • Revhaug A.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.
      • Sànchez-Pérez B.
      • Aranda-Narvaez J.
      • Suarez-Munoz M.
      • Del Fresno M.
      • Fernandez-Aguilar J.
      • Perez-Daga J.
      • et al.
      Fast-track programme in laparoscopic liver surgery: theory of fact.
      • Stoot J.
      • van Dam R.
      • Busch O.
      • van Hillegersberg R.
      • De Boer M.
      • Olde Damink S.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      The effect of multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      • MacKay G.
      • O'Dwyer P.
      Early discharge following liver resection for colorectal metastases.
      • Schultz N.
      • Larsen P.
      • Klarskov B.
      • Plum L.
      • Frederiksen H.
      • Christensen B.
      • et al.
      Evaluation of a fast-track programme for patients undergoing liver resection.
      • Lin D.
      • Li X.
      • Ye Q.
      • Lin F.
      • Li L.
      • Zhang Q.
      Implementation of a fast-track clinical pathway decreases postoperative length of stay and hospital charges for liver resection.
      • Connor S.
      • Cross A.
      • Sakowska M.
      • Linscott D.
      • Woods J.
      Effects of introducing an enhanced recovery after surgery programme for patients undergoing open hepatic resection.
      Figure thumbnail gr1
      Figure 1PRISMA diagram illustrating the identification and selection of studies for review
      Studies investigating outcomes in open hepatic surgery included two randomized controlled trials (RCTs),
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      two prospective cohort studies
      • MacKay G.
      • O'Dwyer P.
      Early discharge following liver resection for colorectal metastases.
      • Schultz N.
      • Larsen P.
      • Klarskov B.
      • Plum L.
      • Frederiksen H.
      • Christensen B.
      • et al.
      Evaluation of a fast-track programme for patients undergoing liver resection.
      and one retrospective cohort study
      • Connor S.
      • Cross A.
      • Sakowska M.
      • Linscott D.
      • Woods J.
      Effects of introducing an enhanced recovery after surgery programme for patients undergoing open hepatic resection.
      and two case–control studies.
      • van Dam R.
      • Hendry P.
      • Coolsen M.
      • Bemelmans H.
      • Lassen K.
      • Revhaug A.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.
      • Lin D.
      • Li X.
      • Ye Q.
      • Lin F.
      • Li L.
      • Zhang Q.
      Implementation of a fast-track clinical pathway decreases postoperative length of stay and hospital charges for liver resection.
      Two case–control trials compared outcomes of ERAS protocols with those of conventional care after laparoscopic surgery.
      • Sànchez-Pérez B.
      • Aranda-Narvaez J.
      • Suarez-Munoz M.
      • Del Fresno M.
      • Fernandez-Aguilar J.
      • Perez-Daga J.
      • et al.
      Fast-track programme in laparoscopic liver surgery: theory of fact.
      • Stoot J.
      • van Dam R.
      • Busch O.
      • van Hillegersberg R.
      • De Boer M.
      • Olde Damink S.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      The effect of multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study.
      The trials included spanned the period from 2008 to 2013. A total of 522 patients underwent liver resection according to an ERAS protocol and 316 were managed on a conventional care pathway following liver resection. The median patient age was 60.0 years (range: 48.4–64.0 years) in the ERAS group and 52.5 years (range: 45.0–67.0 years) in the conventional care group. The majority of the operations were for colorectal liver metastases or hepatocellular carcinoma. Details of participant characteristics are shown in Table 1. All studies explicitly described an ERAS protocol. A median of 11 (range: 8–19) ERAS items were utilized. The individual components utilized and rates of adherence to the protocol are displayed in Table 2.
      Table 1Demographic and operative details reported in the studies of outcomes of enhanced recovery after surgery (ERAS) programmes covered in this review
      van Dam et al
      • van Dam R.
      • Hendry P.
      • Coolsen M.
      • Bemelmans H.
      • Lassen K.
      • Revhaug A.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.
      Sànchez-Pérez et al
      • Sànchez-Pérez B.
      • Aranda-Narvaez J.
      • Suarez-Munoz M.
      • Del Fresno M.
      • Fernandez-Aguilar J.
      • Perez-Daga J.
      • et al.
      Fast-track programme in laparoscopic liver surgery: theory of fact.
      Stoot et al
      • Stoot J.
      • van Dam R.
      • Busch O.
      • van Hillegersberg R.
      • De Boer M.
      • Olde Damink S.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      The effect of multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study.
      Jones et al
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      ERAS/CERAS/CERAS/CERAS/C
      Patients, n61/10026/1713/1346/45
      Age, years, median (range)62 (24–82)/60 (20–81) ns58.3 (29–77)/52.5 (29–84) ns55 (34–82)/45 (26–70) ns64 (IQR 27–83)/67 (IQR 27–84) ns
      ASA class, n (%)
       I11 (18)/14 (14)0/03 (23)/6 (46)0/2 (4.5)
       II42 (69)/64 (64)13 (50)/8 (47)9 (69)/6 (46)43 (93)/38 (84.5)
       III8 (13)/22 (22)13 (50)/9 (53)1 (8)/1 (8)3 (7)/5 (11)
       IV–/––/––/––/–
      nsnsnsns
      Resections, n (%)
       ≥3 segments51 (84)/79 (79) (≥2 segments)0/00/021 (46)/12 (27)
       <3 segments10 (16)/21 (21) (<2 segments)

      ns
      26 (100)/17 (100)

      ns
      12 (92)/12 (92)

      Segmentectomy (≥2)

      1 (8)/1 (8)

      Ns
      25 (54)/33 (73)

      POSSUM score higher in ERAS group (P = 0.012)
      Pathology, n (%)
       CLM51 (84)/72 (72)Malignant35 (76)/26 (58)
       HCC4 (7)/9 (9)3 (12)/3 (18)8 (62)/3 (23)
       Cholangio1 (4)/0 Benign
       Benign4 (7)/14 (14)14 (54)/14 (82)5 (38)/10 (77)1 (2)/9 (20)
       Other metastases2 (3)/4 (4)

      ns
      8 (31)/0

      (P < 0.05)
      ns10 (22)/10 (22)

      (P = 0.021)
      Neoadjuvent therapy, n (%)38 (62)/33 (33) (P = 0.001)NANA36 (78)/25 (56) (P = 0.021)
      CirrhosisNANANANA
      Sex, n (%)
      Male35 (57)/51 (51)

      ns
      15 (58)/10 (59)

      ns
      3 (23)/2 (15) ns31 (67)/23 (51) ns
      EBL, ml, median (range)750 (0–5000)/800 (0–6000) nsTransfusion required ERAS 19.2%; C 5.8% (P < 0.05)50 (50–200)/250 (50–800) (P = 0.002)350 (IQR 174–900)/340 (IQR 150–645) ns
      Operating time, mins, median (range)220 (60–420)/270 (106–510) (P < 0.001)180 (60–345)/177 (80–300) ns118 (85–192)/180 (51–340) nsNA
      Pringle time, mins, mean (SD)NA7 (26.9)/5 (29.4) nsNANA
      Quality (Downs and Black)20/3218/3219/3231/32
      Ni et al
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      Mackay & O'Dwyer
      • MacKay G.
      • O'Dwyer P.
      Early discharge following liver resection for colorectal metastases.
      Schultz et al
      • Schultz N.
      • Larsen P.
      • Klarskov B.
      • Plum L.
      • Frederiksen H.
      • Christensen B.
      • et al.
      Evaluation of a fast-track programme for patients undergoing liver resection.
      Lin et al
      • Lin D.
      • Li X.
      • Ye Q.
      • Lin F.
      • Li L.
      • Zhang Q.
      Implementation of a fast-track clinical pathway decreases postoperative length of stay and hospital charges for liver resection.
      Connor et al
      • Connor S.
      • Cross A.
      • Sakowska M.
      • Linscott D.
      • Woods J.
      Effects of introducing an enhanced recovery after surgery programme for patients undergoing open hepatic resection.
      ERAS/CERAS/CERAS/CERAS/CERAS/C
      80/8012/–100/–56/61128/–
      Mean 48.4 (±15.6)/mean 50.1 (±21.8) (P = 0.57)60 (43–74)/–64 (16–91)/–57 (23–73)/55 (22–81) ns63 (35–82)/–
      7 (95)/78 (98)4 (33.3)/–29 (29)/–(I + II) 43 (76.5)/50 (82)(I + II) 104 (81)/–
      4 (5)/2 (2)7 (58.3)/–46 (46)/–11 (19.5)/10 (16)–/–
      –/–1 (8.3)/–25 (25)/–2 (4)/1 (2)24 (19)/–
      –/––/––/––/––/–
      nsns
      73 (91)/69 (86)3 (25)/–32 (32)/–19 (34)/21 (34)64 (50)/–
      7 (9)/11 (14)

      ns
      9 (75)/–68 (68)/–37 (66)/40 (66)

      ns
      64 (50)/–
      12 (100)77 (77)NA84 (66)/–
      71 (89)/76 (95)12 (12)9 (7)/–
      9 (11)/4 (5)11 (9)/–
      10 (8)/–
      – nsOther 11 (11)14 (11)/–
      NANANANANA
      62 (78)/58 (73) nsNANANANA
      66 (83)/59 (74) ns8 (66.7)/–63 (63)/–31 (58)/34 (56)NA
      Mean 313 (±223.9)/mean 358.2 (±311.7) nsNANA760 (IQR 0–2100)/850 (IQR 0–2300) ns>0.5l 67%, 0.5–1.0l 26%, >1l 7%
      Mean 141.2 (±57.4)/mean 132.1 (±36.9) ns130 IQR (110–160)NA110 (IQR 60–160)/125 (IQR 81–187) nsNA
      NANANANANA
      27/3218/3222/3221/3221/32
      ASA, American Society of Anesthesiologists, C, conventional care; CLM, colorectal liver metastases; EBL, estimated blood loss; IQR, interquartile range; HCC, hepatocellular carcinoma; NA, not assessed; ns, no statistically significant difference; SD, standard deviation. Statistically significant results are highlighted in bold.
      Table 2Care components of enhanced recovery after surgery (ERAS) programmes and adherence data (adherence rates are shown in parentheses)
      van Dam et al
      • van Dam R.
      • Hendry P.
      • Coolsen M.
      • Bemelmans H.
      • Lassen K.
      • Revhaug A.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.
      Sànchez-Pérez et al
      • Sànchez-Pérez B.
      • Aranda-Narvaez J.
      • Suarez-Munoz M.
      • Del Fresno M.
      • Fernandez-Aguilar J.
      • Perez-Daga J.
      • et al.
      Fast-track programme in laparoscopic liver surgery: theory of fact.
      Stoot et al
      • Stoot J.
      • van Dam R.
      • Busch O.
      • van Hillegersberg R.
      • De Boer M.
      • Olde Damink S.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      The effect of multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study.
      Jones et al
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      Ni et al
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      Mackay & O'Dwyer
      • MacKay G.
      • O'Dwyer P.
      Early discharge following liver resection for colorectal metastases.
      Schultz et al
      • Schultz N.
      • Larsen P.
      • Klarskov B.
      • Plum L.
      • Frederiksen H.
      • Christensen B.
      • et al.
      Evaluation of a fast-track programme for patients undergoing liver resection.
      Lin et al
      • Lin D.
      • Li X.
      • Ye Q.
      • Lin F.
      • Li L.
      • Zhang Q.
      Implementation of a fast-track clinical pathway decreases postoperative length of stay and hospital charges for liver resection.
      Connor et al
      • Connor S.
      • Cross A.
      • Sakowska M.
      • Linscott D.
      • Woods J.
      Effects of introducing an enhanced recovery after surgery programme for patients undergoing open hepatic resection.
      Preoperative counsellingXX (100%)XX (100%)XXX
      Avoid bowel prepX (100%)XXX
      Carb drinks up to 2h preoperativelyXXX (100%)XX (100%) Clear fluidsXX
      Avoid anaesthetic pre-medXXX (100%)XXX
      VTE prophylaxisX (100%)X
      Antibiotic prophylaxisX (100%)X (100%)X
      Standard anaesthetic protocolX (95%)XX (100%)X
      Ileus avoidanceXXX (100%)XX Laxatives and chewing gum
      NGT avoidanceX (3/61 had NGT)Removal at end of surgeryXX (100%)XX Removed immediately postoperativelyX
      Intraoperative warmingXX (100%)X
      Minimization of preoperative fluidsXXXX (100%)XX 25% continued IVI beyond PoD 1XXX
      Avoid routine drainsX (1 drain inserted)Drains removed 24–48h postop when usedXX (100%)XX except major resection and this was removed PoD 1XX
      Early removal of IDCXNo IDC in procedures <180minsXX (65%)XXX PoD 1XX
      Multimodal analgesicX Epidural (95%)i.v. matamizol and i.v. paracetamolXX (100%)XX i.v. PCA and paracetamol, then ibuprofenX Epidural followed by gabapentin, celocoxib and paracetamolX Epidural removed PoD 3 then NSAIDSX
      Early feedingX (within 4h in 92%)XXX (100%)XX (supplement drink also)XXX
      Early mobilizationXXXX (100%)XX (100%)XXX
      IDC, indwelling urinary catheter; IVI, intravenous infusion; NGT, nasogastric tube; NSAIDs, non-steroidal anti-inflammatory drugs; PCA, patient-controlled analgesia; PoD, postoperative day; VTE, venous thromboembolism.

      Complications

      All nine studies assessed complication rates.
      • van Dam R.
      • Hendry P.
      • Coolsen M.
      • Bemelmans H.
      • Lassen K.
      • Revhaug A.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.
      • Sànchez-Pérez B.
      • Aranda-Narvaez J.
      • Suarez-Munoz M.
      • Del Fresno M.
      • Fernandez-Aguilar J.
      • Perez-Daga J.
      • et al.
      Fast-track programme in laparoscopic liver surgery: theory of fact.
      • Stoot J.
      • van Dam R.
      • Busch O.
      • van Hillegersberg R.
      • De Boer M.
      • Olde Damink S.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      The effect of multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      • MacKay G.
      • O'Dwyer P.
      Early discharge following liver resection for colorectal metastases.
      • Schultz N.
      • Larsen P.
      • Klarskov B.
      • Plum L.
      • Frederiksen H.
      • Christensen B.
      • et al.
      Evaluation of a fast-track programme for patients undergoing liver resection.
      • Lin D.
      • Li X.
      • Ye Q.
      • Lin F.
      • Li L.
      • Zhang Q.
      Implementation of a fast-track clinical pathway decreases postoperative length of stay and hospital charges for liver resection.
      • Connor S.
      • Cross A.
      • Sakowska M.
      • Linscott D.
      • Woods J.
      Effects of introducing an enhanced recovery after surgery programme for patients undergoing open hepatic resection.
      Median overall complication rates were 25.0% (range: 11.5–46.4%) in ERAS patients, and 31.0% (range: 11.8–46.2%) in conventional care patients. However, Ni et al.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      observed a significantly reduced overall complication rate in the ERAS group (Table 3), and a meta-analysis of overall complication rates in the two RCTs
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      shows that significantly fewer complications occurred after ERAS surgery [I2 = 0%; odds ratio (OR): 0.49, 95% confidence interval (CI) 0.28–0.84; P = 0.01]. Both Jones et al.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      and Ni et al.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      reported significantly fewer non-surgical complications in the ERAS arms of their studies [7.0% versus 27.0% (P = 0.02) in Jones et al.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      ; 12.5% versus 25.0% (P = 0.04) in Ni et al.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      ], but showed no statistically significant difference in the occurrence of liver-specific complications [15.0% in ERAS patients and 11.0% in conventional care patients (P = 0.612) in Jones et al.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      ; 17.5% in ERAS patients and 21.0% in conventional care patients (P = 0.55) in Ni et al.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      )] (TablesS1 and S2, online). Mortality rates were low and were similar in both groups (Table 3).
      Table 3Outcome data reported in studies of the impact of enhanced recovery after surgery (ERAS) programmes
      DesignArm AArm BLoS, A, days, median (range)LoS, B, days, median (range)Functional recovery, A, days, median (range)
      van Dam et al
      • van Dam R.
      • Hendry P.
      • Coolsen M.
      • Bemelmans H.
      • Lassen K.
      • Revhaug A.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.
      Case–controlERAS (n = 61)Conventional care (n = 100)6.0 (3–82) (P < 0.01)8.0 (4–68)NA
      Sànchez-Pérez et al
      • Sànchez-Pérez B.
      • Aranda-Narvaez J.
      • Suarez-Munoz M.
      • Del Fresno M.
      • Fernandez-Aguilar J.
      • Perez-Daga J.
      • et al.
      Fast-track programme in laparoscopic liver surgery: theory of fact.
      Case–controlLaparoscopic ERAS (n = 26)Laparoscopic conventional care (n = 17)2.5 (1–39) ns3 (1–22) nsNA
      Stoot et al
      • Stoot J.
      • van Dam R.
      • Busch O.
      • van Hillegersberg R.
      • De Boer M.
      • Olde Damink S.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      The effect of multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study.
      Case–controlLaparoscopic ERAS (n = 13)Laparoscopic conventional care (n = 13)5.0 (3–10) ns7.0 (3–12) ns3 (1–7) (P = 0.044)
      Jones et al
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      RCTERAS (n = 46)Conventional care (n = 45)4 (IQR 3–5) (P < 0.01)7 (IQR 6–8)3 (IQR 3–4) (P < 0.001)
      Ni et al
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      RCTERAS (n = 80)Conventional care (n = 80)Mean 6.9 (±2.8) (P = 0.018)Mean 8.0 (±3.7)Mean 5.2 (±2.3) (P = 0.0004)
      Mackay & O'Dwyer
      • MacKay G.
      • O'Dwyer P.
      Early discharge following liver resection for colorectal metastases.
      Prospective cohortERAS (n = 12)4 (2–7) daysNA
      Schultz et al
      • Schultz N.
      • Larsen P.
      • Klarskov B.
      • Plum L.
      • Frederiksen H.
      • Christensen B.
      • et al.
      Evaluation of a fast-track programme for patients undergoing liver resection.
      Prospective cohortERAS (n = 100)5 days (minor open); 6 days (major open)NA
      Lin et al
      • Lin D.
      • Li X.
      • Ye Q.
      • Lin F.
      • Li L.
      • Zhang Q.
      Implementation of a fast-track clinical pathway decreases postoperative length of stay and hospital charges for liver resection.
      Case–controlERAS (n = 56)Conventional care (n = 61)7 (3–26) (P < 0.01)11 (4–37)NA
      Conner et al
      • Connor S.
      • Cross A.
      • Sakowska M.
      • Linscott D.
      • Woods J.
      Effects of introducing an enhanced recovery after surgery programme for patients undergoing open hepatic resection.
      Retrospective reviewERAS (n = 128)4 (2–111)NA
      Functional recovery, B, days, median (range)Readmissions AReadmissions BComplications AComplications BMortality
      n (%)n (%)n (%)n (%)n (%)
      van Dam et al
      • van Dam R.
      • Hendry P.
      • Coolsen M.
      • Bemelmans H.
      • Lassen K.
      • Revhaug A.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.
      NA8 (13) ns10 (10) ns25 (41) ns31 (31) nsA = 0 B = 2 (2) ns
      Sànchez-Pérez et al
      • Sànchez-Pérez B.
      • Aranda-Narvaez J.
      • Suarez-Munoz M.
      • Del Fresno M.
      • Fernandez-Aguilar J.
      • Perez-Daga J.
      • et al.
      Fast-track programme in laparoscopic liver surgery: theory of fact.
      NA1 (3.8) ns1 (5.8) ns3 (11.5) ns2 (11.8) nsA = 0 B = 0
      Stoot et al
      • Stoot J.
      • van Dam R.
      • Busch O.
      • van Hillegersberg R.
      • De Boer M.
      • Olde Damink S.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      The effect of multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study.
      5 (2–8)0 ns0 ns2 (15) ns2 (15) nsA = 0 B = 0
      Jones et al
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      6 (IQR 6–7)2 (4) ns0 ns8 (17) ns14 (31) nsA = 1 (2) B = 1 (2) ns
      Ni et al
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      Mean 6.7 (±2.9)NANA24 (30) (P = 0.03)37 (46)A = 0 B = 0 ns
      Mackay & O'Dwyer
      • MacKay G.
      • O'Dwyer P.
      Early discharge following liver resection for colorectal metastases.
      NA3 (25)A = 0
      Schultz et al
      • Schultz N.
      • Larsen P.
      • Klarskov B.
      • Plum L.
      • Frederiksen H.
      • Christensen B.
      • et al.
      Evaluation of a fast-track programme for patients undergoing liver resection.
      6 (6)25 (25)A = 1 (1)
      Lin et al
      • Lin D.
      • Li X.
      • Ye Q.
      • Lin F.
      • Li L.
      • Zhang Q.
      Implementation of a fast-track clinical pathway decreases postoperative length of stay and hospital charges for liver resection.
      NA4 (7.1) ns2 (3.3) ns26 (46.4) ns27 (44.3%) nsA = 1 (2) B = 1 (2) ns
      Conner et al
      • Connor S.
      • Cross A.
      • Sakowska M.
      • Linscott D.
      • Woods J.
      Effects of introducing an enhanced recovery after surgery programme for patients undergoing open hepatic resection.
      14 (11)34 (26.6)A = 2 (1.6)
      C, conventional care; IQR, interquartile range; HCC, hepatocellular carcinoma; LoS, length of stay; NA, not assessed; ns, no statistically significant difference; SD, standard deviation. Statistically significant results are highlighted in bold.

      Length of stay

      The median LoS reported by the studies was 5.0 days (range: 2.5–7.0 days) in ERAS patients and 7.5 days (range: 3.0–11.0 days) in non-ERAS patients. The three cohort studies reported a median LoS of 4.0 days
      • MacKay G.
      • O'Dwyer P.
      Early discharge following liver resection for colorectal metastases.
      • Connor S.
      • Cross A.
      • Sakowska M.
      • Linscott D.
      • Woods J.
      Effects of introducing an enhanced recovery after surgery programme for patients undergoing open hepatic resection.
      and 5.0 days.
      • Schultz N.
      • Larsen P.
      • Klarskov B.
      • Plum L.
      • Frederiksen H.
      • Christensen B.
      • et al.
      Evaluation of a fast-track programme for patients undergoing liver resection.
      All four studies that compared ERAS with conventional management in open liver surgery showed a significantly reduced LoS in the ERAS groups.
      • van Dam R.
      • Hendry P.
      • Coolsen M.
      • Bemelmans H.
      • Lassen K.
      • Revhaug A.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      • Schultz N.
      • Larsen P.
      • Klarskov B.
      • Plum L.
      • Frederiksen H.
      • Christensen B.
      • et al.
      Evaluation of a fast-track programme for patients undergoing liver resection.
      Neither of the two laparoscopic studies
      • Sànchez-Pérez B.
      • Aranda-Narvaez J.
      • Suarez-Munoz M.
      • Del Fresno M.
      • Fernandez-Aguilar J.
      • Perez-Daga J.
      • et al.
      Fast-track programme in laparoscopic liver surgery: theory of fact.
      • Stoot J.
      • van Dam R.
      • Busch O.
      • van Hillegersberg R.
      • De Boer M.
      • Olde Damink S.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      The effect of multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study.
      identified a reduced LoS. However, Stoot et al.
      • Stoot J.
      • van Dam R.
      • Busch O.
      • van Hillegersberg R.
      • De Boer M.
      • Olde Damink S.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      The effect of multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study.
      reported reduced time to achieve functional recovery. Functional recovery was reported by only three studies,
      • Stoot J.
      • van Dam R.
      • Busch O.
      • van Hillegersberg R.
      • De Boer M.
      • Olde Damink S.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      The effect of multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      all of which showed a reduced time to recovery following ERAS care. Five
      • van Dam R.
      • Hendry P.
      • Coolsen M.
      • Bemelmans H.
      • Lassen K.
      • Revhaug A.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.
      • Sànchez-Pérez B.
      • Aranda-Narvaez J.
      • Suarez-Munoz M.
      • Del Fresno M.
      • Fernandez-Aguilar J.
      • Perez-Daga J.
      • et al.
      Fast-track programme in laparoscopic liver surgery: theory of fact.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      • Schultz N.
      • Larsen P.
      • Klarskov B.
      • Plum L.
      • Frederiksen H.
      • Christensen B.
      • et al.
      Evaluation of a fast-track programme for patients undergoing liver resection.
      • Lin D.
      • Li X.
      • Ye Q.
      • Lin F.
      • Li L.
      • Zhang Q.
      Implementation of a fast-track clinical pathway decreases postoperative length of stay and hospital charges for liver resection.
      of the nine trials reported on readmission rates, but observed no significant differences (Table 3).

      Adherence

      Three of the studies reported rates of adherence to the protocol.
      • van Dam R.
      • Hendry P.
      • Coolsen M.
      • Bemelmans H.
      • Lassen K.
      • Revhaug A.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      • MacKay G.
      • O'Dwyer P.
      Early discharge following liver resection for colorectal metastases.
      Jones et al.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      reported 100% adherence in all 19 ERAS categories except the early removal of the indwelling urinary catheter (IDC). Mackay and O'Dwyer
      • MacKay G.
      • O'Dwyer P.
      Early discharge following liver resection for colorectal metastases.
      reported prolonged use of i.v. fluid administration beyond the first postoperative day. Rates of intra-abdominal drain insertion and reduced feeding were also reported (Table 2).

      Parameters of recovery

      Only three
      • Sànchez-Pérez B.
      • Aranda-Narvaez J.
      • Suarez-Munoz M.
      • Del Fresno M.
      • Fernandez-Aguilar J.
      • Perez-Daga J.
      • et al.
      Fast-track programme in laparoscopic liver surgery: theory of fact.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      of the trials reported on the achievement of individual recovery milestones. Time to flatus was significantly reduced in the ERAS groups. Time to establishment of oral diet and time to independent mobilization were either comparable or improved in the ERAS groups when reported (TableS3, online).

      Discussion

      This review investigated the effects of ERAS protocols on recovery following liver resection. Three previous reviews
      • Coolsen M.
      • Wong-Lun-Hing E.
      • van Dam R.
      • van der Wilt A.
      • Slim K.
      • Lassen K.
      • et al.
      A systematic review of outcomes in patients undergoing liver surgery in an enhanced recovery after surgery pathways.
      • Hall T.
      • Dennison A.
      • Bilku D.
      • Metcalfe M.
      • Garcea G.
      Enhanced recovery programmes in hepatobiliary and pancreatic surgery: a systemic review.
      • Spelt L.
      • Ansari D.
      • Sturesson C.
      • Tingstedt B.
      • Andersson R.
      Fast-track programmes for hepatopancreatic resections: where do we stand?.
      have been performed in this area, and have concluded that safety and feasibility were satisfactory and that a reduced LoS does not result in increased morbidity or mortality. However, these reviews
      • Coolsen M.
      • Wong-Lun-Hing E.
      • van Dam R.
      • van der Wilt A.
      • Slim K.
      • Lassen K.
      • et al.
      A systematic review of outcomes in patients undergoing liver surgery in an enhanced recovery after surgery pathways.
      • Hall T.
      • Dennison A.
      • Bilku D.
      • Metcalfe M.
      • Garcea G.
      Enhanced recovery programmes in hepatobiliary and pancreatic surgery: a systemic review.
      • Spelt L.
      • Ansari D.
      • Sturesson C.
      • Tingstedt B.
      • Andersson R.
      Fast-track programmes for hepatopancreatic resections: where do we stand?.
      included studies other than those concerned purely with ERAS versus conventional care, did not report any RCTs and reviewed only two studies comparing ERAS with conventional care after open surgery. Since these reviews
      • Coolsen M.
      • Wong-Lun-Hing E.
      • van Dam R.
      • van der Wilt A.
      • Slim K.
      • Lassen K.
      • et al.
      A systematic review of outcomes in patients undergoing liver surgery in an enhanced recovery after surgery pathways.
      • Hall T.
      • Dennison A.
      • Bilku D.
      • Metcalfe M.
      • Garcea G.
      Enhanced recovery programmes in hepatobiliary and pancreatic surgery: a systemic review.
      • Spelt L.
      • Ansari D.
      • Sturesson C.
      • Tingstedt B.
      • Andersson R.
      Fast-track programmes for hepatopancreatic resections: where do we stand?.
      were released, five studies have been published, including two RCTs. Therefore, in light of this new evidence, it is important to review the current recommendations.
      The present review was limited because the small number of RCTs prevents any meaningful meta-analysis. The majority of studies were observational, which reduces the power of the review and prevents optimal quantitative comparison. However, all trials were procedure-specific and compared ERAS with conventional recovery protocols and thus this review represents the current best available evidence.
      In concordance with the previous reviews on this subject,
      • Coolsen M.
      • Wong-Lun-Hing E.
      • van Dam R.
      • van der Wilt A.
      • Slim K.
      • Lassen K.
      • et al.
      A systematic review of outcomes in patients undergoing liver surgery in an enhanced recovery after surgery pathways.
      • Hall T.
      • Dennison A.
      • Bilku D.
      • Metcalfe M.
      • Garcea G.
      Enhanced recovery programmes in hepatobiliary and pancreatic surgery: a systemic review.
      • Spelt L.
      • Ansari D.
      • Sturesson C.
      • Tingstedt B.
      • Andersson R.
      Fast-track programmes for hepatopancreatic resections: where do we stand?.
      the current review observed that LoS is reduced by ERAS programmes, a result seen in all of the individual studies in open liver resection. However, by contrast with the previous reviews, and in line with the colorectal literature,
      • Kehlet H.
      • Wilmore D.
      Evidence-based surgical care and the evolution of fast-track surgery.
      complication rates in hepatic surgery can also be reduced by ERAS protocols: a meta-analysis of both published RCTs
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      shows a significant reduction in overall complication rates.
      This reduction was not repeated in the non-RCT studies. This may be related to study design and power. However, it is noteworthy that the study conducted by Ni et al.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      featured the youngest population of all the studies and both RCTs
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      included relatively fitter populations. Advanced age and American Society of Anesthesiologists (ASA) class are both independent predictors of morbidity following abdominal surgery
      • Feroci F.
      • Lenzi E.
      • Baraghini M.
      • Vannucchi A.
      • Cantafio S.
      • Scatizzi M.
      Fast-track surgery in real life: how patient factors influence outcomes and compliance with an enhanced recovery clinical pathway after colorectal surgery.
      and it is possible that the younger and fitter populations of these studies
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      • Ni C.
      • Yang Y.
      • Chang Y.
      • Cai H.
      • Xu B.
      • Yang F.
      • et al.
      Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
      progressed better in an enhanced recovery protocol. Furthermore, Jones et al.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      employed an ERAS programme incorporating 19 components – more than in any other trial – and compliance with the protocol was exceptionally high, a key consideration in the conduct of ERAS programmes.
      • Ahmed J.
      • Khan S.
      • Lim M.
      • Chandrasekekaran T.
      • MacFie J.
      Enhanced recovery after surgery protocols – compliance and variations in practice during routine colorectal surgery.
      Adherence was poorly reported: only three trials commented on this aspect. The main areas of reported poor compliance were i.v. fluid restriction, IDC removal and early mobility. Within the literature on ERAS programmes in the context of colorectal surgery, compliance is often not recorded or may be as low as 5%.
      • Ahmed J.
      • Khan S.
      • Lim M.
      • Chandrasekekaran T.
      • MacFie J.
      Enhanced recovery after surgery protocols – compliance and variations in practice during routine colorectal surgery.
      Higher rates of compliance are associated with reduced LoS and reduced compliance is associated with high readmission rates.
      • Ahmed J.
      • Khan S.
      • Lim M.
      • Chandrasekekaran T.
      • MacFie J.
      Enhanced recovery after surgery protocols – compliance and variations in practice during routine colorectal surgery.
      Hence adherence is clearly an area which has potential for improvement in ERAS protocols following liver surgery.
      Although the rates of general complications were observed to have been reduced in the two RCTs, no difference in liver-specific surgical complications was observed. Liver resection offers a unique set of postoperative circumstances as a result of the process of liver regeneration, the anatomical complexity of biliary drainage and intraoperative vascular inflow control, and the transient impairment of liver function following resection. It is therefore not surprising that an ERAS approach does not reduce surgical complications in such patients.
      Whereas ERAS protocols focus on pre- and postoperative considerations, liver surgery provides an opportunity to optimize intraoperative care. The minimizing of blood loss should reduce liver-specific surgical complications.
      • Hammond J.
      • Guha I.
      • Beckingham I.
      • Lobo D.
      Prediction, prevention and management of postresection liver failure.
      • Zimmitti G.
      • Roses R.
      • Andreou A.
      • Shindoh J.
      • Curley S.
      • Aloia T.
      • et al.
      Greater complexity of liver surgery is not associated with an increased incidence of liver-related complications except for bile leak: an experience with 2628 consecutive resections.
      • Poon R.
      • Fan S.
      • Lo C.
      • Liu C.
      • Lam C.
      • Yuen W.
      • et al.
      Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases. Analysis of 1222 consecutive patients from a prospective database.
      Raised central venous pressure (CVP) has been shown to be associated with intraoperative blood loss during liver resection.
      • McNally S.
      • Revie E.
      • Massie L.
      • McKeown D.
      • Parks R.
      • Garden O.
      • et al.
      Factors in perioperative care that determine blood loss in liver surgery.
      Six of the nine trials covered in this review included a care component based on the reduction of intraoperative fluid, but only two
      • van Dam R.
      • Hendry P.
      • Coolsen M.
      • Bemelmans H.
      • Lassen K.
      • Revhaug A.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.
      • Connor S.
      • Cross A.
      • Sakowska M.
      • Linscott D.
      • Woods J.
      Effects of introducing an enhanced recovery after surgery programme for patients undergoing open hepatic resection.
      commented on titration of i.v. fluid according to CVP. Jones et al.
      • Jones C.
      • Kelliher L.
      • Dickinson M.
      • Riga A.
      • Worthington T.
      • Scott M.
      • et al.
      Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
      used goal-directed fluid therapy guided by LiDCO cardiac output monitor to prevent fluid overload, although they did this in the early postoperative period. It would appear that ERAS protocols in liver surgery should incorporate both intraoperative and postoperative components to maximize their gains.
      Areas that were not explored by the studies covered in this review included the use of a thoracic epidural. Although a thoracic epidural is recommended in ERAS in the context of colorectal surgery,
      • Lassen K.
      • Soop M.
      • Nygren J.
      • Cox P.
      • Hendry P.
      • Spies C.
      • the Enhanced Recovery After Surgery (ERAS) Group
      • et al.
      Consensus review of optimal perioperative care in colorectal surgery.
      its use has been questioned in liver surgery.
      • Tzimas P.
      • Prout J.
      • Papadopolous G.
      • Mallett S.
      Epidural anaesthesia and analgesia for liver resection.
      There is evidence suggesting that epidurals may impair recovery in liver surgery, and that alternative methods of analgesia should be considered.
      • Koea J.
      • Young Y.
      • Gunn K.
      Fast track liver resection: the effect of a comprehensive care package and analgesia with single dose intrathecal morphine with gabapentin or continuous epidural analgesia.
      • Revie E.
      • McKeown D.
      • Wilson J.
      • Garden O.
      • Wigmore S.
      Randomized clinical trial of local infiltration plus patient-controlled opiate analgesia vs. epidural analgesia following liver resection surgery.
      Furthermore, a small liver remnant may be a contraindication to the administration of paracetamol.
      • Galinski M.
      • Delhotal-Landes B.
      • Lockey D.
      • Rouaud J.
      • Bah S.
      • Bossard A.
      • et al.
      Reduction of paracetamol metabolism after hepatic resection.
      Paracetamol is routinely utilized as the backbone of analgesic regimens,
      • Hoffmann H.
      • Kettelhack C.
      Fast-track surgery – conditions and challenges in postsurgical treatment: a review of elements of translational research in enhanced recovery after surgery.
      but in major hepatic resections it is often withheld for fear of inducing liver damage, which increases opiate requirements. At present, further evaluation of analgesia in liver surgery within the context of an ERAS programme is required to establish optimal practice.
      This review has highlighted the benefits of the application of enhanced recovery principles following liver surgery. However, the evidence supporting these principles stems from the literature on colorectal surgery. Resectional liver surgery comes with its own set of unique conditions which must be acknowledged when attempting to optimize the outcomes of patients following liver surgery. In order to maximize the potential benefit of such programmes, future research should aim to establish perioperative care plans specific to liver surgery and should accommodate the unique requirements of this operation.
      Length of stay is not an ideal outcome by which to judge the success of an ERAS programme because the factors that make patients able to or keen to leave hospital are many.
      • Maessen J.
      • Dejong C.
      • Kessels A.
      • von Myenfeldt M.
      Length of stay: an inappropriate readout of the success of enhanced recovery programmes.
      Functional recovery was infrequently assessed in the present studies, which offered only modest reporting of recovery milestones. When recovery milestones were reported, ERAS protocols resulted in either parity or some improvement in these outcomes. Both recovery milestones and functional recovery have been suggested as more meaningful than simple LoS in the assessment of the success of an enhanced recovery protocol
      • Coolsen M.
      • Wong-Lun-Hing E.
      • van Dam R.
      • van der Wilt A.
      • Slim K.
      • Lassen K.
      • et al.
      A systematic review of outcomes in patients undergoing liver surgery in an enhanced recovery after surgery pathways.
      and should represent the measurement of success in future programmes.
      In summary, the evidence investigating ERAS following liver surgery is limited and only two RCTS have been conducted. However, postoperative LoS is reduced in the context of ERAS in comparison with that in conventional care. Medical complication rates seem to be reduced, although surgical morbidity remains high and is as yet unaffected by ERAS protocols following liver surgery. Future research should concentrate on perioperative care components specific to liver surgery, such as optimal analgesic regimens and intraoperative manipulations to reduce blood loss, rather than simply transferring components from the literature on colorectal surgery.

      References

        • Kehlet H.
        • Wilmore D.
        Evidence-based surgical care and the evolution of fast-track surgery.
        Ann Surg. 2008; 248: 189-198
        • Scott N.
        • McDonald D.
        • Campbell J.
        • Smith R.
        • Carey A.
        • Johnston I.
        • et al.
        The use of enhanced recovery after surgery (ERAS) principles in Scottish orthopaedic units – an implementation and follow-up at 1 year, 2010–2011: a report from the Muculoskeletal Audit, Scotland.
        Arch Orthop Trauma Surg. 2013; 133: 117-124
        • Lv D.
        • Wang X.
        • Shi G.
        Perioperative enhanced recovery programmes for gynaecological cancer patients.
        Cochrane Database Syst Rev. 2010;
        • Arsalani-Zadaeh R.
        • ElFadl D.
        • Yassin N.
        • MacFie J.
        Evidence-based review of enhancing postoperative recovery after breast surgery.
        Br J Surg. 2011; 98: 181-196
        • Kehlet H.
        Multimodal approach to control postoperative pathophysiology and rehabilitation.
        Br J Anaesth. 1997; 78: 606-617
        • Holte K.
        • Kehlet H.
        Epidural anaesthesia and analgesia – effects on surgical stress response and implications for postoperative nutrition.
        Clin Nutr. 2002; 21: 199-206
        • Grade M.
        • Quintel M.
        • Ghadimi M.
        Standard perioperative management in gastrointestinal surgery.
        Langenbecks Arch Surg. 2011; 396: 591-606
        • Palavecino M.
        • Kishi Y.
        • Chun Y.
        • Brown D.
        • Gottumukkala V.
        • Lichtiger B.
        • et al.
        Two-surgeon technique of parenchymal transection contributes to reduced transfusion rate in patients undergoing major hepatectomy: analysis of 1557 consecutive liver resections.
        Surgery. 2010; 147: 40-48
        • Virani S.
        • Michaelson J.
        • Hutter M.
        • Lancaster R.
        • Washaw A.
        • Henderson W.
        • et al.
        Morbidity and mortality after liver resections: results of the patient safety in surgery study.
        J Am Coll Surg. 2007; 204: 1248-1292
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6: e1000097
        • Coolsen M.
        • Wong-Lun-Hing E.
        • van Dam R.
        • van der Wilt A.
        • Slim K.
        • Lassen K.
        • et al.
        A systematic review of outcomes in patients undergoing liver surgery in an enhanced recovery after surgery pathways.
        HPB. 2013; 15: 245-251
        • Downs S.
        • Black N.
        The feasibility of creating a checklist for the assessment of the methodological quality both of randomized and non-randomized studies of health care interventions.
        J Epidemiol Community Health. 1998; 52: 377-384
        • van Dam R.
        • Hendry P.
        • Coolsen M.
        • Bemelmans H.
        • Lassen K.
        • Revhaug A.
        • the Enhanced Recovery After Surgery (ERAS) Group
        • et al.
        Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.
        Br J Surg. 2008; 95: 969-975
        • Sànchez-Pérez B.
        • Aranda-Narvaez J.
        • Suarez-Munoz M.
        • Del Fresno M.
        • Fernandez-Aguilar J.
        • Perez-Daga J.
        • et al.
        Fast-track programme in laparoscopic liver surgery: theory of fact.
        World J Gastrointest Surg. 2012; 4: 246-250
        • Stoot J.
        • van Dam R.
        • Busch O.
        • van Hillegersberg R.
        • De Boer M.
        • Olde Damink S.
        • the Enhanced Recovery After Surgery (ERAS) Group
        • et al.
        The effect of multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study.
        HPB. 2009; 11: 140-144
        • Jones C.
        • Kelliher L.
        • Dickinson M.
        • Riga A.
        • Worthington T.
        • Scott M.
        • et al.
        Randomized clinical trial on enhanced recovery versus standard care following open liver resection.
        Br J Surg. 2013; 100: 1015-1024
        • Ni C.
        • Yang Y.
        • Chang Y.
        • Cai H.
        • Xu B.
        • Yang F.
        • et al.
        Fast-track surgery improves postoperative recovery in patients undergoing partial hepatectomy for primary liver cancer: a prospective randomized controlled trial.
        Eur J Surg Oncol. 2013; 39: 542-547
        • MacKay G.
        • O'Dwyer P.
        Early discharge following liver resection for colorectal metastases.
        Scott Med J. 2008; 53: 22-24
        • Schultz N.
        • Larsen P.
        • Klarskov B.
        • Plum L.
        • Frederiksen H.
        • Christensen B.
        • et al.
        Evaluation of a fast-track programme for patients undergoing liver resection.
        Br J Surg. 2013; 100: 138-143
        • Lin D.
        • Li X.
        • Ye Q.
        • Lin F.
        • Li L.
        • Zhang Q.
        Implementation of a fast-track clinical pathway decreases postoperative length of stay and hospital charges for liver resection.
        Cell Biochem Biophys. 2011; 61: 413-419
        • Connor S.
        • Cross A.
        • Sakowska M.
        • Linscott D.
        • Woods J.
        Effects of introducing an enhanced recovery after surgery programme for patients undergoing open hepatic resection.
        HPB. 2013; 15: 294-301
        • Hall T.
        • Dennison A.
        • Bilku D.
        • Metcalfe M.
        • Garcea G.
        Enhanced recovery programmes in hepatobiliary and pancreatic surgery: a systemic review.
        Ann R Coll Surg Engl. 2012; 94: 318-326
        • Spelt L.
        • Ansari D.
        • Sturesson C.
        • Tingstedt B.
        • Andersson R.
        Fast-track programmes for hepatopancreatic resections: where do we stand?.
        HPB. 2011; 13: 833-838
        • Feroci F.
        • Lenzi E.
        • Baraghini M.
        • Vannucchi A.
        • Cantafio S.
        • Scatizzi M.
        Fast-track surgery in real life: how patient factors influence outcomes and compliance with an enhanced recovery clinical pathway after colorectal surgery.
        Surg Laparosc Endosc Percutan Tech. 2013; 23: 259-265
        • Ahmed J.
        • Khan S.
        • Lim M.
        • Chandrasekekaran T.
        • MacFie J.
        Enhanced recovery after surgery protocols – compliance and variations in practice during routine colorectal surgery.
        Col Dis. 2011; 14: 1045-1051
        • Hammond J.
        • Guha I.
        • Beckingham I.
        • Lobo D.
        Prediction, prevention and management of postresection liver failure.
        Br J Surg. 2011; 98: 1188-1200
        • Zimmitti G.
        • Roses R.
        • Andreou A.
        • Shindoh J.
        • Curley S.
        • Aloia T.
        • et al.
        Greater complexity of liver surgery is not associated with an increased incidence of liver-related complications except for bile leak: an experience with 2628 consecutive resections.
        J Gastrointest Surg. 2013; 17: 57-64
        • Poon R.
        • Fan S.
        • Lo C.
        • Liu C.
        • Lam C.
        • Yuen W.
        • et al.
        Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases. Analysis of 1222 consecutive patients from a prospective database.
        Ann Surg. 2004; 240: 698-710
        • McNally S.
        • Revie E.
        • Massie L.
        • McKeown D.
        • Parks R.
        • Garden O.
        • et al.
        Factors in perioperative care that determine blood loss in liver surgery.
        HPB. 2012; 14: 236-241
        • Lassen K.
        • Soop M.
        • Nygren J.
        • Cox P.
        • Hendry P.
        • Spies C.
        • the Enhanced Recovery After Surgery (ERAS) Group
        • et al.
        Consensus review of optimal perioperative care in colorectal surgery.
        Arch Surg. 2009; 144: 961-969
        • Tzimas P.
        • Prout J.
        • Papadopolous G.
        • Mallett S.
        Epidural anaesthesia and analgesia for liver resection.
        Anaesthesia. 2013; 68: 628-635
        • Koea J.
        • Young Y.
        • Gunn K.
        Fast track liver resection: the effect of a comprehensive care package and analgesia with single dose intrathecal morphine with gabapentin or continuous epidural analgesia.
        HPB Surg. 2009; 2009: 271986
        • Revie E.
        • McKeown D.
        • Wilson J.
        • Garden O.
        • Wigmore S.
        Randomized clinical trial of local infiltration plus patient-controlled opiate analgesia vs. epidural analgesia following liver resection surgery.
        HPB. 2012; 14: 611-618
        • Galinski M.
        • Delhotal-Landes B.
        • Lockey D.
        • Rouaud J.
        • Bah S.
        • Bossard A.
        • et al.
        Reduction of paracetamol metabolism after hepatic resection.
        Pharmacology. 2006; 77: 161-165
        • Hoffmann H.
        • Kettelhack C.
        Fast-track surgery – conditions and challenges in postsurgical treatment: a review of elements of translational research in enhanced recovery after surgery.
        Eur Surg Res. 2012; 49: 24-34
        • Maessen J.
        • Dejong C.
        • Kessels A.
        • von Myenfeldt M.
        Length of stay: an inappropriate readout of the success of enhanced recovery programmes.
        World J Surg. 2008; 32: 971-997