Feasibility of Enhanced Recovery After Surgery Protocols Implemented Perioperatively in Endoscopic Submucosal Dissection for Early Gastric Cancer: A Single-Center Retrospective Study

Abstract

Background:

Endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) has advantages over traditional radical gastrectomy. We investigated whether enhanced recovery after surgery (ERAS) protocols are appropriate in the ESD perioperative period.

Materials and Methods:

We screened 129 consecutive patients, and 12 were excluded. All study patients underwent ESD for EGC. Of the 117 included patients, 57 received traditional perioperative care between January 2017 and December 2018, and 60 patients received perioperative care according to ERAS protocols between January 2019 and September 2020. The primary study endpoint was ESD-related complications. Secondary endpoints included the following postoperative parameters: anal exhaust time, incidence of nausea or vomiting, length of hospitalization, fever rate, abdominal pain on the visual analog scale (VAS), and reported perioperative satisfaction.

Results:

Complications were comparable between the 2 groups. In the ERAS group, no patients experienced delayed bleeding or perforation. One traditional group patient bled, and one perforated. Postoperative anal exhaust time, nausea or vomiting incidence, hospitalization, fever rate, and VAS pain scores were significantly lower, and perioperative satisfaction rate was significantly higher in the ERAS group.

Conclusions:

ERAS protocols are both feasible and safe for patients undergoing ESD. ERAS protocols enhance the advantages of ESD for EGC without increasing complications.

Introduction

Enhanced recovery after surgery (ERAS) is a multimodal, multidisciplinary clinical strategy to care for patients undergoing surgery. ERAS protocols require a team consisting of surgeons, anesthetists, nurses, and staff from units that care for patients undergoing surgery.¹ As reported in previous studies, ERAS can reduce morbidity rates and shorten the length of hospital stay.^2,3 ERAS was started by Kehlet,⁴ primarily to manage colorectal surgery. However, it has been shown to improve clinical outcomes in several major surgical specialties, such as orthopedics, urology, gynecology, and upper gastroenterology.^5–9

Endoscopic submucosal dissection (ESD) is gradually being accepted as a treatment for early gastric cancer (EGC), limited to the mucosa without lymph node metastasis. ESD is a treatment option that helps preserve most of the gastric function compared with radical surgical resection. It helps achieve a similar oncological outcome with lower complications, shorter hospital stays and costs, and higher patient satisfaction.¹⁰

The perioperative management of ESD mainly depends on clinical experience, which currently lacks guidelines or consensus. It remains unclear whether management strategies for ERAS and ESD may clash in the future. This study investigated the benefits of ERAS protocols implemented in the perioperative period of ESD for patients with EGC. It also aimed to examine whether ERAS protocols can magnify the advantages of ESD without increasing complications.

Materials and Methods

Study population

A total of 129 consecutive patients with 131 gastric epithelial neoplasia, including EGC and intraepithelial neoplasia, were considered for enrollment in this retrospective single-center study at the Gansu Provincial Hospital. In total, 12 patients were excluded because they did not meet the inclusion criteria, and thus, 117 patients were eventually enrolled in the study. Of these, 57 patients with EGC underwent ESD between January 2017 and December 2018 and received traditional treatment. Additionally, 60 patients with EGC underwent ESD with ERAS treatment between January 2019 and September 2020. All ESD procedures were performed by the same medical team. The clinical data of the patients in the 2 groups are shown in Table 1.

Table 1.

Clinical Characteristics and Pathology of the Study Population

Variable	All patients, n = 117	ERAS group, n = 60	Traditional group, n = 57	P
Age (years)	55.0 ± 10.8	54.9 ± 10.1	55.1 ± 11.6	.983
Gender (male/female)	50/67	27/33	23/34	.611
BMI (kg/m²)	22.8 ± 2.1	22.7 ± 2.5	22.9 ± 1.7	.914
Depth of invasion				.501
Mucosal	103	54	49
Upto 1/3 of submucosal	14	6	8
Specimen size of cancer	41.5 ± 11.3	42.5 ± 15.9	40.5 ± 13.8	.877
Pathological grade				.101
High-grade intraepithelial neoplasia	59	27	32
Low-grade intraepithelial neoplasia	24	11	13
Differentiated	31	20	11
Undifferentiated	3	2	1
En bloc resection				.678
Yes	107	56	51
No	10	4	6
Curative resection				.471
Yes	110	57	53
No	7	3	4
ASA score				.824
Class I	73	39	34
Class II	33	16	17
Class III	11	5	6
Operation times (minutes)	78.4 ± 10.2	81.5 ± 13.8	75.2 ± 9.6	.552

Data are presented as n or mean ± SD.

ASA, American Society of Anesthesiologists; BMI, body mass index; ERAS, enhanced recovery after surgery; SD, standard deviation.

Eligibility criteria

The inclusion criteria were as follows: (1) initial diagnosis of EGC or intraepithelial neoplasia with histological evidence; (2) complied with the criteria of the Japan Gastroenterological Endoscopy Society¹¹; and (3) signed informed consent that their clinical data might be used in future studies.

The exclusion criteria were as follows: (1) bleeding-related risks (oral antiplatelet agents or anticoagulants); (2) additional gastrectomy after non-curative ESD procedure; (3) presence of mental disorder; and (4) limited capability for mobilization.

ESD operation

The patients were anesthetized with endotracheal intubation and positioned on the left side. ESD was performed with single accessory channel endoscope (EPK-i5000; Pentax Co., Ltd., Tokyo, Japan). Dots were drawn to mark around the lesion with an ∼0.3 cm margin with argon plasma coagulation. A mixture of glycerol, sodium chloride, and diluted epinephrine (1:10,000) was injected into the submucosal layer to lift the lesion from the muscle layer using a 21-gauge needle. Additionally, a circumferential incision was made outside the marking dots (0.5 cm), and dissection was made on the surface of the muscle layer using a dual knife or insulation-tipped diathermic knife until the lesion was eradicated. Bleeding or exposed small vessels were treated with electrocoagulation or a titanium clip.

ERAS protocols

The ERAS program includes 12 items. There are two preoperative protocols (patient education and fasting before surgery) and five perioperative protocols (warmth preservation, infusion restriction, anesthesia, placing nasogastric tube, and mucosal defect closure). Data on the five remaining protocols were collected postoperatively, including suppression of postoperative nausea and vomiting (PONV), analgesia control, postoperative education, liquids limitation, and fasting protocol. The detailed treatments received by the 2 groups are shown in Table 2.

Table 2.

Enhanced Recovery After Surgery Protocols in Endoscopic Submucosal Dissection

Perioperative management	ERAS group	Traditional group
Days before surgery
Patients education	Informed consentIntroduce ERAS through mobile phone app	Informed consent
Fasting	Prohibited solids 6 hours and clear liquid 2 hours before operation	Prohibited solids 12 hours and clear liquid 8 hours before operation
Perioperative
Warming	Blanket	None
Fluid restriction	Yes	No
Anesthesia	Tracheal intubation	Tracheal intubation
Nasogastric	No	Place when high risk
Defect closure	Purse-string suture as routine	Purse-string suture when high risk
Postoperative
Inhibition of nausea or vomiting	Administer immediately after ESD	Administer upon occurrence
Analgesia	NSAIDs when needed	Opioid or NSAIDs when needed
Extra informative assistance	Through phone app 16 hours online per day	Ward round two times per day
Fluid restriction	Less than 1000 mL/day	2000–2500 mL/day
Fasting	Intake clear liquid 6 hours and liquid diet 12 hours after ESD	Liquid diet after anal exhaust

ERAS, enhanced recovery after surgery; ESD, endoscopic submucosal dissection; NSAIDs, nonsteroidal anti-inflammatory drugs.

Endpoint and outcome assessment

All patients underwent gastroscopic screening on the first postoperative day after ESD as a second check to ensure that there was no active bleeding or perforated risks, as well as 1 week and 1 month after ESD to screen for wound healing.¹² The primary endpoint was ESD-related complications such as perforation and bleeding. The secondary endpoints included the length of hospital stay after ESD, anal exhaust time after the operation, incidence of PONV 24 hours postoperatively, hospitalization, postoperative fever rate (body temperature over 38°C), patient satisfaction with guidance (scale 0–10, 0 indicated highly unsatisfactory outcome, 10 indicated most satisfactory outcome), and results of visual analog scale (VAS) assessment 6 and 12 hours after surgery for measuring abdominal pain.^13,14

Statistical analyses

All statistical analyses were performed using IBM SPSS Statistics for Windows, version 25 (IBM Corp., Armonk, NY, USA). Normally distributed measurement data are expressed as mean ± standard deviation, independent sample t-test was used to compare the groups, and dichotomous or categorical variables were analyzed using the chi-square test or Fisher's exact probability method. Differences were considered statistically significant at P < .05.

Results

Study population and pathology of ESD

A total of 129 consecutive patients who underwent ESD were assessed for study eligibility, and 12 patients were excluded as follows: 3 patients with uncurative resection who underwent additional laparoscopic gastrectomy, 7 patients with increased bleeding risk, 1 patient with limited mobilization, and 1 patient with depressive disorder. A total of 117 patients were included (50 men and 67 women; mean age, 55 years; Fig. 1). The body mass index (BMI) of all patients was 22.8 ± 2.1 kg/m². The baseline age, sex, and BMI showed no significant differences between the ERAS and traditional groups.

FIG. 1.

Patient enrollment flowchart.

The depth of invasion, specimen size of EGC, and pathological grade distribution between the 2 groups were not significantly different. The tumor mainly affected the mucosal layer, and the specimen sizes were 42.5 ± 15.9 mm and 40.5 ± 13.8 mm in the ERAS and traditional groups, respectively. Pathological examination showed no significant difference in En bloc resection and curability between the 2 groups (P = .678 and P = .471, respectively). The operation times were 81.5 ± 13.8 and 75.2 ± 9.6 minutes in the ERAS and traditional groups, respectively.

Outcomes of ERAS implemented in ESD

Complications between the ERAS and traditional groups were not significantly different. In the traditional treatment group, 2 patients experienced complications. One patient experienced delayed bleeding 2 days after ESD with a sign of tarry stool. A gastroscopic screen revealed errhysis, and argon plasma coagulation was used to coagulate the hemorrhagic spot, followed by fasting water and food for 3 days. The patient was discharged 6 days after treatment and recovered fully. The other patient suffered acute abdominal pain 1 day after ESD and was diagnosed with perforation.

Fortunately, the perforation occurred at midnight on an empty stomach and did not cause severe abdominal contamination. We performed gastroscopy and clipped the small hole using a titanium clip. The anal exhaust time in the ERAS group was shorter than that in the traditional group (P = .048). Nausea or vomiting rate after surgery was lower than that in the traditional group (P = .043). In addition, the hospitalization time after operation for the ERAS and traditional groups was 35.6 ± 12.2 and 77.9 ± 15.1 hours, respectively (P < .001). Furthermore, the fever rate, satisfaction with guidance, and 12 hours of VAS were significantly better in the ERAS group. The clinical outcomes of the 2 groups are shown in Table 3.

Table 3.

Clinical Outcomes

Category	ERAS group	Traditional group	Statistical outcome	P
Anal exhaust time (hours)	23.5 ± 6.8	39.2 ± 6.9	t = −2.807	.048
Nausea or vomiting rate	12 (20)	21 (36.8)	χ² = 4.095	.043
Hospital stay (hours)	35.6 ± 12.1	77.9 ± 15.1	t = 16.682	.000
30-Days readmission rate	0 (0)	1 (1.8)		.487
Complications	0	2		1
Delayed bleeding	0	1
Perforation	0	1
Fever rate	5 (8.3)	13 (21.1)	χ² = 4.704	.030
Satisfaction of guidance	8.0 ± 0.9	5.2 ± 1.4	t = 2.914	.044
6 Hours of VAS after ESD	3.2 ± 0.9	5.9 ± 1.5	t = −2.673	.056
12 Hours of VAS after ESD	3.2 ± 0.6	5.0 ± 0.9	t = −2.882	.045

Data are presented as n (%) or mean ± SD.

ERAS, enhanced recovery after surgery; ESD, endoscopic submucosal dissection; SD, standard deviation; VAS visual analog scale.

Discussion

Based on the study findings, it is reasonable to apply ERAS protocols to ESD for EGC. The overall incidence of postoperative complications (including perforation and bleeding) after ESD for EGC in Asia and Western countries is as low as 3.5%–9.5%.^15–17 However, based on airway management concerns and the potential for reflux and aspiration of secretions or blood, it is strongly recommended to use general anesthesia during gastric ESD surgery.^18,19 We have used general anesthesia in our center since beginning with the ESD procedure, for the aforementioned reasons. The mean operation time of ESD for EGC is 60–141 minutes,^20,21 and the ESD procedure is minimally invasive, but prolonged general anesthesia can lead to a systemic stress response.²² Additionally, the median length of hospital stay after ESD for EGC is 3–6 days.^23–25 The traditional ESD procedure for EGC needs further modification; thus, we implemented this study.

To the best of our knowledge, this is the first study to evaluate the feasibility and safety of ERAS protocols implemented in ESD procedures. After accumulating experience by using ERAS protocols in radical gastric surgery patients and obtaining better clinical outcomes, we adopted ERAS protocols in ESD for EGC. The results show that ERAS protocols can amplify the advantages of ESD for EGC without increasing complications. Furthermore, ERAS protocols decrease hospitalization time after surgery, accelerate postoperative anal exhaust, and promote patient satisfaction compared with traditional protocols.

Our ERAS protocol is based on that of the ERAS society.²⁶ The key principles included perioperative counseling, nutrition strategy optimization, standardized anesthetic and analgesic regimens, avoidance of a nasogastric tube, restriction of intravenous fluids, and early mobilization.

Early oral intake is a fundamental part of ERAS protocols and has been verified in early and advanced gastric cancer cases for both open and laparoscopic radical gastrectomy. Increasing evidence shows no significant difference between the early oral intake and traditional delayed feeding strategies of different types of radical surgery for gastric cancer.^27–29 From a physiological perspective, the total volume of saliva secreted is minimal (500–600 mL, on average), and secretion will increase when eating or drinking.³⁰ In addition to gastric juice, a large amount of liquid passes over the gastric operation wound each day. Therefore, early oral intake of clear liquids is physiologically safe. Oral intake can also stimulate recovery of gastrointestinal motility.³¹ In our study, early oral intake did not cause more complications than traditional management. This is similar to previous studies.^32,33

We used mobile phone apps to help patients and their family members better understand ERAS protocols and to help answer their questions immediately after ESD procedures, for 16 hours/day. For elderly patients who were unfamiliar with cell phones, family members or caregivers assisted with communication. Consequently, patients were more satisfied than the traditional group with the guidance provided. This system helped us explain ESD protocols to patients rather than simply signing an informed consent form and collecting feedback during ward rounds twice per day. Mobile apps can help bridge the communication gap between doctor and patient, and their positive impact on clinical outcomes has been verified for many diseases.^34–36 Findings from our study support this conclusion.

Although the ERAS guidelines do not emphasize the improvement of surgical techniques, the surgery itself and the improvement of details are the basis of ERAS. Evidence has shown that closing the gastric mucosal defect appears reasonable and effective for preventing bleeding, even in high bleeding risk patients,^37–39 and it promotes healing of post-ESD mucosal defects histologically according to in vivo porcine models.⁴⁰ We performed routine prophylactic purse-string suture closure of the gastric mucosal defect in the ERAS group and in high-risk (muscle layer injury, blood vessel exposure, or more electrical coagulation) patients of the traditional group (21/57).

No bleeding or perforation was observed in the ERAS group. Due to purse-string sutures in our ERAS group, the operation time was longer than that in the traditional group (81.5 ± 13.8 versus 75.2 ± 9.6 minutes, P = .581); however, no significant difference was detected in terms of outcomes. The fever rate after ESD in the ERAS group was significantly lower than that in the traditional group, which might indicate that the purse-string suture prevents systemic inflammation response.

Abdominal pain after ESD is mostly caused by intraoperative insufflation of excessive carbon dioxide into the gastrointestinal tract through gastroscopy. In addition, a local inflammatory reaction to the dissected mucosal layer above the muscle layer can lead to mild abdominal pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended in the ERAS protocols, whereas opioid drugs are not recommended in ERAS protocols, as they hinder the recovery of gastrointestinal function.⁴¹ In this study, NSAIDs were administered to the ERAS group after ESD when needed. Sometimes, only one dose (15/27) was administered.

There was decreased incidence of PONV in the ERAS group. The ERAS protocol includes a routine single intravenous dose of ondansetron, compared with intravenous administration as needed for the traditional group. Also, shortened hospitalization is one of most important indicators of ERAS program implementation.¹⁰ In the present study, ERAS protocols significantly reduced length of hospital stay after ESD from 77.9 ± 15.1 to 35.6 ± 12.1 hours.

There were a few limitations to this study. First, this was a retrospective study. Some information that reflects systemic inflammation is incomplete and is not included. Thus, a large volume randomized prospective study is needed in the future. Additionally, the long-term impact of ERAS protocols on oncological outcomes needs to be investigated. Last but not least, ERAS protocols for EGC are used as bundled care methods to accelerate patient recovery. It remains unclear how much the effects of each protocol contribute to the result.

Conclusions

To the best of our knowledge, this is the first study to evaluate the feasibility and safety of ERAS protocols implemented in ESD for EGC. ERAS can amplify the advantages of ESD without increasing complications. Furthermore, ERAS can improve patient satisfaction with guidance, reduce hospitalization time after surgery, accelerate anal exhaust, and reduce abdominal pain and PONV after surgery, compared with the traditional group.

Footnotes

Authors' Contributions

J.L.: Conceptualization, methodology, formal analysis, writing—original draft preparation, visualization, and funding acquisition. G.K., T.L., and Z.L.: Resources, data curation, and investigation. T.G.: Supervision, project administration, and writing—reviewing and editing.

Ethics Approval and Consent to Participate

This retrospective study was approved by the Research Ethics Committee of Gansu Provincial Hospital (2021–328).

Consent for Publication

Consent for publication was obtained from all participants.

Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by the Natural Science Foundation of Gansu Province (Grant No. 20JR10RA372), Health Industry Research Project of Gansu Province (Grant No. GSWSKY-2019-03), National scientific research project support program of Gansu Provincial Hospital (Grant No. 19SYPYB-10), Open fund project of Gansu Key Laboratory of Molecular Diagnosis and Precision Therapy of Surgical Oncology (Grant No. 2020GSZDSYS02), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (Grant No. NLDTG2020020), Scientific Research and Innovation Fund of Gansu University of Chinese Medicine (Grant No. 2020KCYB-7), and Longyuan Youth Innovation and Entrepreneurship Talent Project (Grant No. 111266548053).

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