This study had a three-center, retrospective cohort design. A total of 227 lesions in 198 consecutive patients who underwent ESD for superficial esophageal neoplasia at Southern-Tohoku General Hospital in Fukushima, Hyogo Prefectural Awaji Medical Center in Hyogo Prefecture, and Kitano Hospital in Osaka between April 2011 and November 2017 were included in the study.

The following outcomes were compared between patients who underwent the procedure under GA and those who received DS: the primary outcome was the ESD procedure time, and the secondary outcomes were the complications associated with ESD, i.e., perforation, postoperative hemorrhaging, and aspiration pneumonia, and complications associated with anesthesia. In addition, we isolated the following potential confounding factors from electrical medical records to secure the validity of the comparison: age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) physical status classification [14], site, diameter, and circumference of the lesion; resected diameter and circumference of the lumen; dissection speed; en bloc resection rate; number of devices used; and rate of use of the clip-with-line method. In the DS group, we evaluated the rate of unintended DS. Systolic blood pressure <90 mm Hg was defined as hypotension, heart rate <50 beats/min as bradycardia, respiratory rate <8 breaths/min as bradypnea, and SpO₂ <90% as hypoxemia.

This study was approved by the ethics committees of all participating institutions and conducted in accordance with the 1975 Declaration of Helsinki.

ESD was performed using a single-channel endoscope with a water jet system (GIF-Q260J; Olympus Medical Systems Co., Tokyo, Japan), with CO₂ insufflation (UCR; Olympus Medical Systems). A Dual knife (KD-650Q; Olympus Medical Systems) was used for the procedure, and a Hook knife (KD260LR; Olympus Medical Systems) was added as needed.

Sodium hyaluronate (0.4%, MucoUp; Seikagaku Co., Tokyo, Japan) was locally injected into the submucosa using a 25-G injection needle (Needle Master; Olympus Medical Systems). Hemostatic graspers (Coagrasper; FD-411QR; Olympus Medical Systems) were used for preventive coagulation and intraoperative hemostasis of vessels. A VIO300D (ERBE Elektromedizin Gmbh, Tübingen, Germany) was used as the electrosurgery unit. In this study, all of the surgeons in each facility were Certified Surgeons of the Japanese Gastroenterological Endoscopy Society, each with experience performing more than 30 cases of esophageal ESD and more than 100 cases of gastric ESD.

The procedure time was defined as the time from the beginning of the submucosal injection to complete removal. The average dissection speed was calculated by dividing the time of the procedure by the area of the resected specimen, which was calculated as 3.14×0.25×long axis×minor axis. The procedure time included delays due to movement of the patient during the procedure.

Esophageal perforation was defined as macroscopic perforation to the esophageal wall, and postoperative hemorrhaging was defined as post-ESD hematemesis requiring an endoscopic procedure, bleeding accompanied by melena, anemia (decrease of ≥ hemoglobin 2 g/dL), or a condition requiring transfusion.

In this study period, all patients were allocated to receive DS or GA during the operation, at the physician’s discretion.

The principal of DS was established by the ASA [14]. In brief, an initial dose of 7.5 mg pentazocine and 2 mg midazolam for patients weighing <50 kg or 3 mg midazolam for patients weighing ≥50 kg was administered. In response to patients’ body movements, 1 mg midazolam or 7.5 mg pentazocine was additionally administered. After completing ESD, 0.5 mg flumazenil was administered to awaken the patients.

In the GA group, a propofol intravenous drip of 1–2 mg/ kg/min was administered, 3% sevoflurane was administered for tracheal intubation, and 0.6–0.9 mg/kg rocuronium was administered as a muscle relaxant. Intraoperative sevoflurane was maintained at 1%–1.5%, and 0.3–0.5 µg/kg/min remifentanil was administered as an adjuvant.

All agents were administered by a gastroenterologist who was not involved in the ESD procedure. Oxygen at 2 L/min was administered via a nasal cannula in the endoscopy room, and 3-lead electrocardiography, pulse oximetry, and automatic blood pressure monitoring were performed to monitor vital signs and oxygen saturation, with recordings made every 5 min.

The chi-squared test, Kruskal-Wallis exact test, or Fisher’s exact test were used to compare categorical variables. Continuous variables were expressed as median and range. Median values of continuous data were compared using the Mann-Whitney U-test. All statistical analyses were performed using the IBM SPSS software program (IBM Co., Armonk, NY, USA). All tests were two-tailed, and a p-value of <0.05 was considered statistically significant.

Patient characteristics are summarized in Table 1. Among 198 patients with esophageal neoplasia, ESD under GA was performed in 102 patients (51.5%), and ESD under DS was performed in 96 patients (48.5%). There were no significant differences in age, sex, BMI, comorbidities, or use of antithrombotic drugs between the GA and DS groups. Patients with a poorer ASA score were more common in the GA group than in the DS group.

There were significant differences in the size of tumors (p<0.001), tumor circumference of the lumen (p=0.042), and histologic type (p=0.030) between the groups. There were no significant differences in the location of tumors, depth of invasion, or lymphatic and vascular invasion (Table 2). Although there was no significant difference between the 2 groups in terms of the resected diameter, the GA group had a significantly higher proportion of patients with a lumen circumference ≥2/3 (p=0.005).

Table 3 shows the outcomes. The ESD procedure times for the GA and DS groups were 28 (5–202) and 40 (8–249) min, respectively (p<0.001), indicating a significantly shorter procedure time in the GA group. There were no significant differences in the incidence of complications between the 2 groups. In the DS group, intraoperative perforation occurred in 2 patients (1.8%) and aspiration pneumonia occurred in 2 patients (1.8%). The perforation in 1 patient was not from trauma to the muscle layer caused by the knife but rather from a large rupture caused by intraoperative eructation. As the perforation was large and could not be sutured with clips, surgical drainage was performed. The other patient’s perforation was induced by trauma to the muscle layer caused by a knife and was successfully sutured with clips. There were no marked differences in the en bloc resection rates between the 2 groups. The dissection speed was significantly higher in the GA group than in the DS group (p<0.001). The number of patients who required the use of multiple devices was significantly higher in the DS group than in the GA group (p=0.001), but the rate of use of the clip-with-line method [15,16] was comparable between the 2 groups.

In the DS group, the median total amount of midazolam was 10.8 (4.0–27.0) mg and the median total amount of pentazocine was 7.5 (0–30) mg. The median number and amount of bolus injections of midazolam were 2 (0–12) times and 2.0 (0–12) mg, respectively. The median number and amount of bolus injections of pentazocine were 0 (0–3) times and 0 (0–22.5) mg, respectively. The median frequency of body movement during ESD was 2 (0–14) times.

There were no complications associated with GA and no mortalities among the enrolled patients. In the DS group, hypotension occurred in 7 patients (6.3%), bradycardia occurred in 5 patients (4.5%), hypoxemia occurred in 2 patients (1.8%), and bradypnea occurred in 3 patients (2.7%). No patients required assisted mask ventilation or intubation. A paradoxical response during sedation occurred in 3 patients (2.7%), but ESD was successfully completed under DS.