Impact of Enhanced Recovery After Surgery on Long-Term Outcomes and Postoperative Recovery in Patients Undergoing Hepatectomy: A Retrospective Cohort Study

Figures & data

Table 1 Summary of the ERAS Protocols and Comparison with Conventional Perioperative Management

Period	ERAS Group	Non-ERAS Group
Preoperative period	Preoperative counseling: advised by surgeon, anesthesiologist, and nurse about the surgery and anesthesia type and perioperative risk	Advised by a surgeon about surgery risk
	Written detailed recovery plan
	Perioperative nutrition: surgery should be postponed to improve nutritional status when diagnosed with body weight loss 10–15% in 6 months, BMI<18.5kg/m2 and serum albumin <30g/L	None
	Preoperative fasting and preoperative carbohydrates load: allow clear liquid until 2 h before surgery	Fasting/no solid food 8 hours before surgery
	Allow solid foods until 6 h before surgery	Fasting/liquid 4 hours before surgery
	Oral carbohydrate solution loading over two days prior to surgery
	Anti-thrombotic prophylaxis: wear compression stockings before surgery	None
	Optimization of comorbidities	No strict requirements
	Smoking and alcohol advice
	Daily exercise: walk 1 hour per day between first consultation and surgery	No strict requirements
	Preoperative bowel preparation	Routine mechanical bowel preparation
	No routine mechanical bowel preparation
Intraoperative period	Pre-anesthetic medication: short-acting anxiolytics used to relieve anxiety prior to the induction of anesthesia (dexmedetomidine)	None
	Anesthesia: total intravenous anesthesia was used	Violate or violate combined with intravenous anesthesia was used
	Optimization of fluid balance by target-directed fluid therapy	Fixed fluid strategy
	Preventing intraoperative hypothermia	None
	Active warming with a warming blanket
	Warm intravenous fluid with a liquid warming tube
	Mini incision: surgical incision depends on the patient’s abdominal shape and tumor location in the liver. Mercedes-type incision should be avoided due to higher incisional hernia risk	Dependent on the accessibility for the surgeon
	Prevention of delayed gastric emptying (DGE): the omentum flap should cover the cut surface of the liver to reduce the risk of DGE after left-sided hepatectomy	None
	Perioperative steroids administration: steroids used before hepatectomy in normal liver parenchyma and not given in diabetic patients	None
	Antimicrobial prophylaxis and skin preparation: single dose intravenous antibiotics should be administered before skin incision and less than 1 h before hepatectomy	Depends on the risk of postoperative infection risk
Postoperative period	Postoperative analgesia: comprehensive, quantitative, and dynamic evaluation combined with preventive multi-mode analgesic management (eg, PCEA +NSAIDs +wound infusion)	Selective on-demand/symptomatic treatment
	Prophylactic nasogastric intubation: not used	Depends on surgery risk
	Preventing postoperative nausea and vomiting (PONV): multimodal approach to PONV should be used	Selective on-demand/symptomatic treatment
	Early mobilization: should be encouraged from the morning after the operation until hospital discharge: walk 10–20 m on POD1, walk 100 m on POD2, walk 100 m+ on POD3	Mobilization was started at 2–3 d after surgery
	Stimulation of bowel movement: chewing gum encouraged to stimulate gut motility	Individualized liver blood flow control technique
	Postoperative glycemic control: insulin therapy to maintain normoglycemia is recommended	Individualized liver blood flow control technique
	Consider removal of pelvic drainage as early as possible	Care decided by the surgeon
	Audit: systematic audit improves compliance and clinical outcome in healthcare practice	None

Table 2 Clinical Characteristics of the Patients Undergoing Hepatectomy Between ERAS Group and Non-ERAS Group

Variable	Original Cohort		P	Matched Cohort		P
	ERAS Group (n=463)	Non-ERAS Group (n=632)		ERAS Group (n=463)	Non-ERAS Group (n=463)
Age (years)	63.2±8.6	62.8±9.2	0.465	63.2±8.6	62.8±9.2	0.495
Sex (n, %)			0.870			0.786
Female	72(15.6%)	96(14.8%)		74(15.6%)	70(15.6%)
Male	391(84.4%)	536(85.2%)		389(84.4%)	393(84.4%)
BMI kg/m2, (median-IQR)	22.3 (21.5–25.4)	23.6 (21.7–25.6)		22.5 (21.6–25.2)	23.6 (21.7–25.6)
ASA (n, %)			0.341			0.992
I	32(6.9%)	39(6.2%)		32(6.9%)	32(6.9%)
II	395(85.3%)	528(83.6%)		395(85.3%)	396(85.3%)
III	36(7.8%)	65(10.2%)		36(7.8%)	35(7.8%)
Patients enrolled (n, %)			0.968			0.998
2014	112(24.2%)	149(23.6%)		112(24.2%)	112(24.2%)
2015	106(22.9%)	139(22.0%)		106(22.9%)	104(22.9%)
2016	125(27.0%)	176(27.8%)		125(27.0%)	127(27.0%)
2017	120(25.9%)	168(26.6%)		120(25.9%)	120(25.9%)
CCI (n, %)			0.404			0.989
0	256(55.3%)	345(54.6%)		256(55.3%)	254(55.3%)
1	132(28.5%)	166(26.3%)		132(28.5%)	134(28.5%)
≧2	75(16.2%)	121(19.1%)		75(16.2%)	75(16.2%)
Hepatitis B surface antigen (n, %)			0.604			0.945
Negative	160(34.6%)	228(36.1%)		160(34.6%)	159(34.6%)
Positive	303(65.4%)	404(63.9%)		303(65.4%)	304(65.4%)
Child-Pugh classification (n, %)			0.366			0.835
A	412(88.9%)	551(87.2%)		412(88.9%)	410(88.9%)
B	51(11.1%)	81(12.8%)		51(11.1%)	53(11.1%)
Serum AFP (ug/L)			0.383			0.928
≤ 20	74(15.9%)	89(14.1%)		74(15.9%)	73(15.9%)
>20	389(84.1%)	543(85.9%)		389(84.1%)	390(84.1%)
Tumor size (n, %)			0.698			0.895
≤5cm	215(46.4%)	286(45.2%)		215(46.4%)	213(46.4%)
>5cm	248(53.6%)	346(54.8%)		248(53.6%)	250(53.6%)
Tumor number (n, %)			0.421			0.855
Single	393(84.9%)	525(83.2%)		393(84.9%)	391(84.9%)
Multiple	70(15.1%)	107(16.8%)		70(15.1%)	72(15.1%)
Tumor encapsulation (n, %)			0.426			0.867
No/incomplete	376(81.2%)	525(83.1%)		376(81.2%)	374(81.2%)
Yes	87(18.8%)	107(16.9%)		87(18.8%)	89(18.8%)
Vascular invasion (n, %)			0.502			0.768
No	405(87.5%)	544(86.1%)		405(87.5%)	402(87.5%)
Yes	58(12.5%)	88(13.9%)		58(12.5%)	61(12.5%)
Liver cirrhosis (n, %)			0.617			0.997
No	42(9.0%)	51(8.1%)		42(9.0%)	42(9.0%)
Mild	256(55.3%)	347(54.9%)		256(55.3%)	253(55.3%)
Moderate	83(17.9%)	104(16.4%)		83(17.9%)	84(17.9%)
Severe	82(17.8%)	130(20.6%)		82(17.8%)	84(17.8%)
BCLC stage (n, %)			0.335			0.989
0	31(6.7%)	39(6.1%)		31(6.7%)	31(6.7%)
A	409(88.3%)	548(86.7%)		409(88.3%)	408(88.3%)
B	23(5.0%)	45(5.0%)		23(5.0%)	24(5.0%)
Estimated blood loss (n, %)			0.665			0.944
≤ 400 mL	312(67.4%)	418(66.2%)		312(67.4%)	313(67.4%)
> 400 mL	151(32.6%)	214(33.8%)		151(32.6%)	150(32.6%)
Blood transfusion (n, %)			0.785			0.932
No	381(82.3%)	516(81.6%)		381(82.3%)	380(82.3%)
Yes	82(17.7%)	116(18.4%)		82(17.7%)	83(17.7%)
Pathology diagnosis (n, %)			0.091			0.979
HCC	376(81.2%)	509(80.6%)		376(81.2%)	374(81.2%)
ICC	53(11.4%)	58(9.4%)		53(11.4%)	55(11.4%)
CHC	32(7.4%)	65(10%)		32(7.4%)	32(7.4%)
Operative methods (n, %)			0.618			0.860
Open	101(21.8%)	130(20.6%)		101(21.8%)	103(21.8%)
Laparoscopic	362(78.2%)	502(79.4%)		362(78.2%)	360(78.2%)
Anesthesia method (n, %)			0.309			0.895
GA	31(6.7%)	40(6.3%)		31(6.7%)	30(6.7%)
GA+GEA	432(93.3%)	592(93.7%)		432(93.3%)	433(93.3%)

Abbreviations: HCC, hepatocellular carcinoma; ICC, cholangiocarcinoma; CHC, combined hepatocellular carcinoma and cholangiocarcinoma.

Figure 1 Flow diagram detailing the selection process for patients included in this retrospective analysis.

Table 3 Univariate Analysis of OS and DFS

Variables	OS		DFS
	HR (95% CI)	P-value	HR (95% CI)	P-value
ERAS Protocol (no vs yes)	1.60(1.03,3.73)	<0.001	1.34(1.27,2.60)	<0.001
Age (years)	1.07(1.01,1.14)	0.030	1.10(1.03,1.18)	0.010
Gender (male)	0.63(0.38,5.15)	0.665	0.92(0.53,1.59)	0.764
Liver cirrhosis (Yes)	0.70(0.39,1.27)	0.237	0.17(0.03,1.17)	0.072
AFP (>20ng/mL)	1.69(1.13,2.53)	0.011	1.44(1.04,1.98)	0.026
Tumor encapsulation (None)	2.36(1.02,5.42)	0.044	1.55(0.90,2.67)	0.115
Tumor staging (III–IV)	1.80(1.66,3.35)	0.066	1.47(1.06,2.04)	0.022
Tumor size (>5cm)	1.39(0.72,2.70)	0.323	1.20(0.78,1.83)	0.410
Tumor number (Multiple)	1.22(0.72,2.06)	0.462	1.37(0.91,2.08)	0.132
Vascular invasion (Yes)	3.45(1.83,6.53)	<0.001	2.38(1.34,4.21)	0.003
ASA (III–IV)	1.89(1.14,3.14)	0.013	2.77(1.17,6.54)	0.021
Surgical procedure (Video-assisted)	1.10(0.41,2.97)	0.845	1.34(0.52,3.41)	0.545
Blood loss (>400mL)	1.35(0.52,3.52)	0.538	1.09(0.63,1.90)	0.751
Blood transfusion (yes)	1.26(0.90,1.42)	0.234	1.45(0.82,1.62)	0.651
Postoperative complication (yes)	1.32(0.82,1.52)	0.315	1.56(0.62,1.73)	0.358
Anesthesia time (>3h)	1.39(0.66,2.93)	0.395	1.34(0.59,3.04)	0.482

Table 4 Multivariable Cox Proportional of OS and DFS

Variables	OS (Before Matching)		OS (After Matching)		DFS (Before Matching)		DFS (After Matching)
	HR (95% CI)	P-value	HR (95% CI)	P-value	HR (95% CI)	P-value	HR (95% CI)	P-value
ERAS Protocol (no vs yes)	1.18(1.07,2.02)	<0.001	1.13(1.02,2.12)	0.013	1.80(1.53,2.71)	<0.001	1.46(1.32,2.62)	0.016
Age (years)	1.04(1.00,1.09)	0.018			1.07(1.02,1.12)	0.006
AFP (>20ng/mL)	1.57(1.08,2.11)	0.022			1.25(0.84,1.85)	0.267
Tumor encapsulation (None)	2.06(0.76,3.46)	0.157			NA
Tumor staging (III–IV)	NA				1.12(0.76,1.66)	0.576
Vascular invasion (Yes)	2.55(1.34,4.86)	0.004			1.89(1.25,2.84)	0.002
ASA (III–IV)	1.75(1.04,2.56)	0.039			2.34(1.04,3.39)	0.045

Figure 2 (A) Disease-free survival curves from the date of surgery between ERAS group and non-ERAS group; (B) overall survival curves from the date of surgery between ERAS group and non-ERAS group.

Abbreviations: DFS, disease-free survival; OS, overall survival.

Figure 3 (A) Readmission rate and mortality between the ERAS group and non-ERAS group; (B) hospital length of stay between groups. (C) The percentage of postoperative complications between groups according to Clavien-Dindo classification; (D) postoperative complications between groups. *P<0.001.