Enhanced recovery after surgery (ERAS) decreases recovery time and improve the recovery effect versus for elective gastric cancer surgery: a single-center randomized controlled trial

Enhanced recovery after surgery (ERAS) can help patients improve recovery speed, improve patient satisfaction, reduce postoperative pressure and reduce postoperative hospital stay. This study evaluated ERAS feasibility and effectiveness compared with conventional perioperative care and their signicance in gastrectomy for patients with gastric cancer. Methods This article is a prospective cohort analysis of 272 patients. This paper investigates tumor morphology, operation information, exhaustion time, ambulation time, walking distance on the operation day and 1 day, 2 days and 3 days after the operation, While blood test indexes related to postoperative recovery and postoperative complications are evaluated.

Surgical treatment is still the only hope of cure. However, open resection is associated with severe trauma, numerous complications, slow recovery, prolonged hospital stay and many other perioperative complications. Laparoscopic radical gastrectomy is the rst choice for the treatment of gastric cancer.
For advanced gastric cancer, there is a high risk of recurrence and metastasis. Postoperative chemotherapy can improve the survival rate. Gastric cancer surgery is a complex operation with high risk related to postoperative stress, complications and sequelae. As poor postoperative recovery may delay the start of chemotherapy, surgeons pay more attention to methods to accelerate postoperative recovery.
The term enhanced recovery after surgery (ERAS) came into practice for the rst time in 2002. Later, in 2009, emerging data from preliminary studies guided the issuance of the rst consensus guidelines. Soon, principles rst adopted in colorectal surgery became more commonly applied in other procedures.
However, speci c ERAS guidelines for gastric cancer were not published until 2014 (ERAS-GC). In China, the concept of ERAS was rst introduced and promoted in 2007 by Li. In the same year, Li's team rst reported the safety and effectiveness of ERAS in patients with gastric cancer.
Enhanced recovery after surgery (ERAS) is a multidisciplinary approach to perioperative care with evidence-supported measures to reduce surgical stress and accelerate postoperative rehabilitation.
Typical ERAS protocols involve preoperative counselling, reduced fasting times, avoidance of bowel preparation, optimized anesthesia protocols, use of multimodal anesthesia, avoidance of nasogastric tubes and intraabdominal drains, early mobilization and early progression to food. 6  1) diagnosis of gastric adenocarcinoma con rmed by a preoperative gastroscopy and pathological biopsy.
2) curative gastrectomy without simultaneous resection of other organs.
3) the age is between 18 and 80. 4) non-emergency surgery. 5) no radiotherapy or chemotherapy before the operation. 6) the tumor has no long-term metastasis.
The ERAS group exclusion criteria were as follows: Patients can also withdraw from the study after enrollment if any of the following conditions occur: a) radical resection cannot be performed for any reason; b) serious complications occur during or after surgery that requires rescue measures; c) patients or their families request to withdraw from the study.

Data collection
All data were retrieved from the patients' clinical records. The items studied were the patients' characteristics, tumor pro le, surgical information, postoperative data and postoperative complications. Patient characteristics evaluated include age, gender, body mass index (BMI), Nutritional Risk Screening (NRS) 2002 score and the risk grade of the American Society of Anesthesiologists (ASA) score. The pathological tumor stage (TNM classi cation) are also included. Surgical-related data included the kind of procedure and the type of reconstruction. Postoperative data included the time of the rst atus. The amount of diet on the operation day, the rst day, the second day and the third day after operation were also collected. The time to get out of bed for the rst time and the walking distance on the day of operation, the rst day, the second day and the third day after the operation were gathered. Maximum pain on a visual analog scale (VAS, evaluated at operation day, the rst, second and third day after surgery), postoperative hospital stays, postoperative complications are also collected. Blood samples were collected 1 day before surgery and the rst day, the third day and the fth day after surgery, the collected samples were used to analyze C-reactive protein (CRP) and Leukocyte Count (WBC) detection.

ERAS program
The ERAS program can be divided into preoperative, intraoperative and postoperative phases. Detailed information about the treatment and perioperative care was explained to the patients on admission. 8, The 3.Preoperative physical examination to assess nutritional status and rule out contraindications to surgery.
4.Chest breathing training: inhale deeply through the nose until respiratory exhaustion, hold the breath for one to two seconds ( this exercise can prolong the exchange time of oxygen and carbon dioxide in the lung, so that more oxygen enters the blood). Retract the lips, as by whistling, slowly exhale from the mouth and empty as you exhale. Six to eight times a day for 10 minutes. (take a rest after every 5 deep breaths) balloon blowing training to exercise your lung function is also applicable.
5.Teach correct and effective method of coughing and expectoration: before expectoration, cough gently for several times to loosen the sputum, then take a deep breath in the mouth, hold the breath, pause for a moment, cough once or twice with short force, discharge the sputum, and unfold your hands and press the abdomen, which can help you exert force and protect the wound after surgery.
6.Do physical exercise according to your physical strength every day.
7.If you suffer from severe malnutrition, i.e. weight loss ≥ 5% in one month, pleural effusion and ascites, or 70% − 100% reduction in food intake (compared with the requirement) in the last week, we will give oral nutritional supplements. For those who can't eat, we will give preoperative intravenous drip of nutrient solution.
8.Nutritional risk screening and intervention: all patients with gastrointestinal cancer were screened with NRS (2002) nutritional risk screening table. For patients with a total score of ≥ 3, oral enteral nutrition is recommended routinely; for patients with eating di culties, parenteral nutrition solution can be used before and after the operation.
Day before surgery 1.No routine bowel preparation (except in incidences of constipation).
2.Drink 600-1200ml of clear uid 12 hours before the operation, such as Maltodextrin fructose.
3.Anesthesia consultation, skin preparation, blood examination, insertion of indwelling gastric tube and urinary catheter, and prophylactic antibiotics.
a The gastric tube could be removed when the amount of drainage was ≤ 100 mL/d; the drained uid was not blood-tinged, and atus had been passed. b The abdominal drainage tube could be removed when abdominal infection, anastomotic stula, and other postoperative complications were ruled out, and the drainage volume was ≤ 10 mL/d for 2 days.

Time point Protocol
Day of surgery 1.Drink 200 ml Carbohydrate electrolyte solution 2 hours before operation; responsible ward nurse will communicate with the operating room to determine the operation time and clear liquid time as far as possible.
2.Electric blanket and abdominal-temperature saline irrigation to maintain body temperature during surgery.
3.Decision to use abdominal drainage tubes depended on the surgical conditions of antibiotics.
5.Routine prevention of nausea and vomiting for 2-3 days.
6.Attempt to drink warm water (about 20 mL/h) after the patient revived.
Postoperative day 1 1.After operation, water can be taken orally under the guidance of medical staff, and the amount of water will gradually increase according to the recovery of intestinal peristalsis and tolerance. According to the doctor's advice: after the recovery of general bowel sounds liquid diet can commence, anal exhaust after surgery into a semi-liquid diet, high protein, high vitamin, low fat and low sugar diet is recommended for patients who could not meet the nutritional needs after oral administration were given intravenous nutrition supplement.
2.Early mobilization encouraged and establish activity diary. On the rst day after the operation, bed activity should be 1-2 hours, divided into 10-15 minutes, 50-100 meters each time. After that, they should get out of bed for 4-6 hours every day, 1000-2000 meters per day. After the operation, the hip and ankle pump, limb massage and turning over cough and expectoration were started as soon as possible.
3.Gastric tube removed according to accepted criteria for extubation a 4.Intermittent urinary catheterization started to train the bladder and stopped when bladder sensation returned to normal. Catheter tube should be removed according to accepted criteria for extubation.
a The gastric tube could be removed when the amount of drainage was ≤ 100 mL/d; the drained uid was not blood-tinged, and atus had been passed. b The abdominal drainage tube could be removed when abdominal infection, anastomotic stula, and other postoperative complications were ruled out, and the drainage volume was ≤ 10 mL/d for 2 days.

Time point Protocol
Postoperative day 2-7 1.Encouragement to continue and prolong out-of-bed activities.
2.Oral uid intake needs to be increased, liquid diet (such as small amounts of rice soup) started, intravenous uids reduced.
3.Antibiotics stopped if there was no evidence of infection.
4.Gastric tube removed if not obstructed. a 5.If urinary catheter was not obstructed, b it was removed after completion of bladder training.
a The gastric tube could be removed when the amount of drainage was ≤ 100 mL/d; the drained uid was not blood-tinged, and atus had been passed. b The abdominal drainage tube could be removed when abdominal infection, anastomotic stula, and other postoperative complications were ruled out, and the drainage volume was ≤ 10 mL/d for 2 days.
Conventional perioperative care (Traditional program) Patients in the conventional surgery group received conventional perioperative care: 1) f fasting for 10 hours before the operation, stopping uid intake 6 hours before operation; 2) bowel preparation (enemas and oral antibiotics), 3) nasogastric tube and peritoneal drainage tube placement, 4) administration of general anesthesia, 5) resumption of diet after the rst atus, and 6) resumption of ambulation 2-3 days after surgery.
Patients in the traditional perioperative care group were allowed to eat a liquid diet until lunch of the day before surgery and no food was allowed after dinner. Endotracheal intubation was performed under general anesthesia. Anesthesia was general anesthesia without a combination of local preemptive analgesia. Postoperative pain was managed by PCA only. NSAIDs were not routinely used in the CC group. Additional painkillers were not routinely given and additional analgesics were administered only when the patient complained about pain. A nasogastric tube was used for stomach decompression before surgery and removed after the bowel function recovered completely.
Postoperative treatment consisted of parenteral nutrition of fat emulsion, amino acids and glucose (11%) injection, which was administered until atus. At that time, the nasogastric tube was removed and the patients were advised to drink water. After full intestinal recovery, the diet consisted of a clear liquid diet, then a full liquid diet, and nally a soft diet. In the CC group, the urinary catheters were removed 2-3 days after surgery. Drains routinely were used and the drainage tubes were removed 5 or 6 days after operation if the drainage uid was clear and the amount of drainage discharge was less than 100 mL/ day.
Ambulation was encouraged 24 hours after surgery in this group and all patients were mobilized on the second day of surgery in the CC group.

Discharge criteria
Patients were discharged based on the following criteria: 1) normal body temperature; 2) adequate pain control with oral medication; 3) absence of nausea and/or vomiting; 4) good atus and/or defecation; 5) ability to tolerate non-elemental diet and soft food without intravenous nutritional support; 6) mobilization without assistance; 7) normal laboratory data; 8) no postoperative complications; and 9) acceptance of discharge by the patient.

Follow-up
In the ERAS group, the patients kept in touch with us by an outpatient service or telephone after discharge within the rst 24 hours and once weekly for 4 weeks. The patients could also contact us if they had any discomfort.  Table 2).
After statistical analysis, we found that there were no signi cant differences between the ERAS group and the CC group in terms of age (P = 0.338), gender (P = 0.574), BMI (P = 0.298), NRS 2002 score (P = 0.144), ASA score (P = 0.943) and TNM classi cation (P = 0.164) (

Surgical procedures and outcomes
Surgical approach There was no statistical signi cance in the surgical approach between the ERAS and CC groups (P = 0.136) ( Table 3). The percentage of Laparoscopic-assisted in the ERAS group was 73.33%, and 80.92% in the CC group.

Type of operation
There was no statistical signi cance in the type of operation between the ERAS and CC groups (P = 0.190) ( Table 3). The percentage of Total gastrectomy in the ERAS group was 83.33%, and 88.81% in the CC group.  It can be seen from Table 4 that the daily food intake of the ERAS group and CC group on the day of operation, rst day after operation, second day after operation and third day after operation are statistically different (P < 0.001). CC group did not have food on the day of operation, rst day and second day after operation, while in the ERAS group, some patients could have food on the day of operation. Through Table 4, we can indicate that the daily food intake of patients in the ERAS group was increasing within the four days after operation.
There was also a signi cant difference in the time of rst ambulation after operation between ERAS group and CC group (P < 0.001  Pain control VAS analysis showed that pain intensity of patients in the ERAS group was signi cantly lower than that of patients in the CC group on 1 hour (P < 0.001), 1 day (P < 0.001), 2 days (P < 0.001) and 3 days (P < 0.001) after operation (Table 5). Postoperative surgical stress and in ammatory response The response induced by systemic surgical stress was assessed by measuring the white blood cell (WBC) count and C-reactive protein levels. When comparing the WBC count before surgery between the groups, there was no statistical signi cance (P = 0.564) ( Table 6). The WBC count in both groups was elevated on the rst day after operation, but compared to the ERAS group on the rst day after operation, the WBC in the CC group was signi cantly higher (P = 0.001). The white blood cell (WBC) count on the rst day after operation is 12.51 ± 3.34 in the ERAS group and 14.45 ± 1.81 in the CC group. The WBC count in the ERAS group and CC group both began to drop on the third day after operation, but there are also statistical signi cances on the third day (P = 0.023) and fth day (P = 0.001) after operation between the ERAS group and CC group.
For the in ammatory marker C-reactive protein, there was no statistical signi cance between the ERAS and CC groups before surgery (P = 0.280) ( Table 4). There was statistical signi cance for C-reactive protein on the rst day, third day and fth day after operation between the two groups (P < 0.01) ( Table 4). .79 mg/dL at the fth day after surgery in CC group. Furthermore, compared with the CC group, the level of CRP in the ERAS group was also lower on the rst day (P < 0.001), third day (P < 0.001) and fth day (P < 0.001) after operation. Abbreviations: ERAS, enhanced recovery after surgery; CC, conventional care; CRP, C-reactive protein;

Postoperative complications
No statistical signi cance was found between the incidences of postoperative complications in the ERAS and CC groups (P = 0.943) (Supplementary Table 1

Discussion
In the present study, we demonstrated the effectiveness and feasibility of our ERAS program in gastric cancer patients who underwent radical gastrectomy by open surgery or laparoscopy. Compared with the conventional perioperative care group, the ERAS group had a faster rst atus (P < 0.001), faster rst ambulation (P < 0.001), further walking distance (P < 0.001) after operation, patients experienced lesser pain (P < 0.001) and had a shorter postoperative (P < 0.001). These ndings are consistent with those of previous studies.
Wilmore and Kehlet rst reported the ERAS programs, which apply a series of optimized perioperative measures with evidence-based medicine to reduce surgical trauma and stress, to accelerate postoperative rehabilitation, and to shorten the length of stay. 26, ERAS was rst used after colorectal cancer surgery, and then, ERAS protocols have been gradually accepted as being able to optimize clinical outcomes, value and experience for patients with GC. , 8 Subsequently, certain gastric cancer treatment centers have applied ERAS programs to gastrectomy , that con rms their safety and effectiveness.
Expediting postoperative bowel function and advancing of diet are important targets of ERAS protocols and were successfully achieved in GC-ERAS group. In a similar Japanese study with an HC group, 35 the rst atus occurred one day earlier and the rst bowel movement occurred two days earlier in the GC-ERAS group. This result was further veri ed in a randomized prospective study by Wang et al., 34 who reported that atus occurred one day earlier in patients on an ERAS protocol.
Early oral feeding was safe. 21 17,21 Early postoperative enteral nutrition with dietary ber could accelerate recovery of peristalsis, protect gut mucosal barrier function, alleviate intestinal barrier dysfunction, decrease the incidence of bacterial translocation and enhance the recovery of gut function. 24 In the present study, most patients who underwent ERAS tolerated early oral diet well. Although gastroparesis occurred in some patients, the symptoms mostly occurred in the initial stage of oral diet and did not develop into severe complications (P = 0.675). Several studies showed that ERAS resulted in signi cantly reduced postoperative hospital stays for gastrectomy. 34  Preoperative oral administration of carbohydrates, which is extensively recognized as an important component of ERAS programs, accelerates the early release of insulin and avoids postoperative insulin resistance and excessive protein degradation. However, preoperative oral carbohydrates do not improve postoperative nutritional status or contribute to maintaining muscle strength. 21 The time to initial liquid diet intake, out-of-bed activity period and time to postoperative gastrointestinal function recovery were signi cantly shorter than those in the control group under the premise of the same recovery effect.
The ERAS concept emphasizes that patients get out of bed, ingest a liquid diet, and undergo removal of the gastrointestinal decompression tube and catheter earlier to promote postoperative intestinal function recovery and accelerated rehabilitation.
While surgical resection is still the only option to cure gastric cancer, it can lead to a strong stress response. Stress inhibits immune function and stimulates the production of several in ammatory mediators, which further inhibit immune function. These changes result in increased postoperative complications, delayed recovery after surgery, and other adverse effects. 23 The core mechanism of ERAS is that multimodal interventions may lead to a major reduction in the undesirable sequelae of surgical injury, and stress-free surgery is the key goal of ERAS. Robust evidence suggested that ERAS played an important role in attenuating the surgical stress response and accelerating the return to baseline in colorectal cancer surgery 18 , which was afforded eloquent proof in GC surgery. The in ammatory factors, such as CRP, IL-6 and tumor necrosis factor α, are related to the extent of tissue injury caused by surgery.
CRP is an in ammatory protein synthesized and secreted by the liver in the acute phase of stress. It can activate complement, promote granulocyte proliferation, and enhance macrophage phagocytosis.
Postoperative elevation in serum CRP level is closely related to the degree of surgical trauma. CRP can re ect acute stress and in ammatory response with high sensitivity and speci city. Some researchers have reported that CRP is an independent predictor of prognosis in gastric cancer patients. 30 In our study, the difference in CRP level between the two groups suggest that the application of ERAS reduced the in ammatory response in gastric cancer patients.
C-reactive protein (CRP), an important systemic in ammatory biomarker, is extensively used in clinical settings for infection diagnosis. , This is in accordance with the clinical experience that abnormal CRP level is very common in the early days after surgery. Considering a possible physiological uctuation by transient bacterial contamination during the operation or preparation of intestinal anastomosis. The authors concluded that such results indicated that CRP on POD3 could be used for early oral diet advancement within an ERAS program. , The reason for the remarkably enhanced diagnostic capacity of CRP may be that, on the fth day after surgery, the mixing effects such as surgical trauma, blood loss, or absorption of necrotic tissues that are known to increase CRP levels were usually well controlled.
Garcia-Granero et al. published a study with 250 patients after colorectal operation and likewise found that CRP on POD5 was an eligible marker for early discharge, as its speci city was 83% and NPV was 98%. 26 Benoit et al. suggested that a CRP before POD5 of < 100 mg/L was reassuring and may permit the patient to leave the hospital in safe conditions. , ERAS aims to improve outcomes and promote early discharge by emphasizing preoperative patient education, shortening the duration of preoperative fasting, supplying preoperative carbohydrates, no bowel preparation, active prevention of hypothermia, no routine use of nasogastric tubes, controlling pain su ciently without opioids, providing early ambulation, and quickly advancing the return to a normal diet.
Studies have found that some procedures in gastrectomy, for example, routine nasogastric decompression were unnecessary because early oral feeding enhances the postoperative gastrointestinal tract recovery and decreased the duration of hospital stay without increasing complications.
ERAS encompassed a combination of preoperative, intraoperative and postoperative measures to enhance the postoperative recovery in surgical procedures. Compared with conventional care, ERAS could reduce the stress response and organ dysfunction, shorten the duration to atus and defecation, accelerate the decrease in CRP and WBC, and thereby greatly shorten the postoperative stay, fasten the recovery of gut function, shorten the time required for overall recovery and increase patients' satisfaction. 34,,, Our results were consistent with the ndings of other studies. 36 We found that in our study, ERAS was able to reduce postoperative stress and in ammation. In the present study, we found that patients after gastrectomy in the ERAS group had a shorter hospital stay (P < 0.001) and postoperative complications had no statistical signi cance (P = 0.943).
Preoperative patient education through contact between patients and staff can avoid the anxiety and perioperative stress reactions, which promotes faster recovery. Optimal pain control plays a fundamental role in postoperative care. Postoperative pain is one of the most important factors that delays postoperative recovery by not only increasing surgical stress but also affecting the mobilization of patients. , The results showed that pain intensity in the ERAS group was signi cantly lower than that of the CC group (P < 0.001). Wang et al7 reported that the rst day of atus after gastrectomy was faster in patients who received ERAS care than in those who received conventional care. Our result is similar to his ndings (P < 0.001), times to rst atus in the ERAS group were 54.60 ± 17.41 hours and 76.71 ± 9.47 hours in the CC group. Prolonged perioperative fasting, preoperative bowel preparation, and nasogastric tube intubation were likely to delay bowel-function recovery. Previous studies have shown that the small intestine might return to normal enteroinesia 6 hours after abdominal surgery and that liquid can be easily absorbed in the small intestine in early postoperative recovery.

Conclusion
ERAS can reduce postoperative stress, enhance the recovery of the gut, reduce pain intensity, shorten hospital stays and increase satisfaction in gastric cancer patients undergoing curative gastrectomy.