Dexmedetomidine-pethidine combination for sedation during esophageal endoscopic submucosal dissection

Introduction

Endoscopic submucosal dissection (ESD) allows for en-bloc resection of large lesions, enabling accurate histopathological assessment of disease curability (1,2). This minimally invasive technique has become a cornerstone treatment for early-stage gastrointestinal tumors (3). However, ESD procedures require careful manipulation and can be time-consuming. Esophageal ESD presents a particular challenge due to the thin esophageal wall and narrow lumen, which limit endoscopic maneuverability (4). Therefore, adequate sedation and minimizing patient movement are crucial for successful ESD execution.

Midazolam (MDZ) (Dormicum; Astellas Pharma, Tokyo, Japan), a GABA receptor agonist with sedative properties, is commonly used in Japan for endoscopic procedures (5). While reported as beneficial during gastric ESD (6,7), MDZ can sometimes induce paradoxical reactions like increased agitation. This risk is particularly high in heavy alcohol consumption (8), as alcohol consumption increases the activity of cytochrome p450 enzymes, leading to rapid metabolism of benzodiazepines like MDZ (9,10). Given the prevalence of heavy alcohol consumption among esophageal cancer patients (11,12), MDZ may not provide reliable sedation for this population. Moreover, involuntary body movements associated with disinhibition during inadequate sedation can significantly hinder ESD performance (13) and potentially necessitate procedure termination.

Dexmedetomidine (DEX) hydrochloride (Precedex; Hospira Japan Co., Ltd, Osaka, Japan), an alpha-2 receptor agonist, offers analgesic, sympathomimetic, and sedative effects. Unlike some sedatives, DEX has minimal impact on respiration (14), contributing to its growing use in intensive care units (15). Recent studies indicate that DEX also induces less patient movement during endoscopic procedures compared to MDZ (16,17). However, DEX can suppress cardiovascular responses (hypertension and tachycardia) by blocking the sympathetic response to pain. This can lead to potential side effects like bradycardia and hypotension.

There is a lack of standardized guidelines for sedation during ESD, leading to variation in practice across hospitals. While previous studies explored the use of DEX for esophageal ESD, they often combined it with other sedatives to achieve deeper sedation, which can increase the risk of hemodynamic instability (13,18). Our institution utilizes a combination of DEX and pethidine hydrochloride for esophageal ESD based on the principle that combining analgesics and sedatives provides optimal anesthesia during the procedure.

For patients with esophageal cancer, many of whom have a history of heavy alcohol consumption, DEX is preferred over MDZ due to concerns about paradoxical reactions with the latter. Pethidine, a narcotic analgesic, helps reduce the gag reflex. To date, no research has investigated the efficacy and safety of the DEX-pethidine combination specifically for esophageal ESD sedation. This study, therefore, aimed to evaluate the anesthetic efficacy and safety of this combined approach during esophageal cancer ESD. We present this article in accordance with the STROBE reporting checklist (available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-7/rc).

Methods

We enrolled 245 consecutive patients who underwent esophageal cancer ESD at the Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan, between April 2020 and December 2022.

Patients were included if they met the following criteria: diagnosis of superficial esophageal cancer confirmed by endoscopic biopsy or endoscopic observation, ESD candidacy without requiring intubation, preoperative computed tomography scan showing no lymph node or distant metastasis, and a performance status between 0 and 2.

Exclusion criteria included: cervical lesions with obstructed oral view; large tumors exceeding an expected treatment time of 2 hours; underlying heart disease, arrhythmia, or respiratory disease requiring oxygen at rest; unstable angina (new or worsening within 3 weeks of ESD); and myocardial infarction within 6 months of ESD.

Following these criteria, 210 patients who received DEX-pethidine sedation during esophageal ESD were included in the final analysis (Figure 1).

Figure 1 Flow chart of patients enrolled in this study. ESD, endoscopic submucosal dissection.

Medications and sedation protocol

All patients received 1 L of extracellular fluid before the procedure. Prophylactic oxygen was not administered. To minimize discomfort, the pharynx was locally anesthetized with a 2% topical lidocaine jelly before sedation began.

Sedation was administered by a gastroenterologist skilled in providing basic and advanced cardiac life support. This ensured immediate access to resuscitation equipment, which is always available in endoscopy rooms.

The target sedation level during ESD was a score of 1 or 2 on the Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S) (Table 1) (19). This scale helps gauge patient responsiveness. DEX was administered continuously. The initial loading dose was 6 µg/kg/h for ten minutes, followed by a maintenance dosage of 0.4 µg/kg/h.

Following the initial DEX load, endoscopic therapy commenced. Additionally, a bolus dose of pethidine (17.5–35 mg) was administered, adjusted based on the patient’s body size and age. Pethidine was given again in 17.5 mg increments if facial expressions suggested agitation during the procedure, 1 h after the last dose, or if the MOAA/S score increased to 3 or higher. The DEX maintenance dose remained constant throughout the procedure and was discontinued once ESD was completed, and the endoscope removed (Figure 2).

Figure 2 Sedation protocol. DEX, dexmedetomidine; ESD, endoscopic submucosal dissection.

Monitoring

Intraoperatively, all patients underwent electrocardiography and were equipped with an automated blood pressure meter and pulse oximeter. This allowed for continuous monitoring of heart rate, oxygen saturation (SpO₂), and blood pressure (measured every 3 minutes). Furthermore, a nurse monitored the patient’s consciousness level using the MOAA/A scale every 15 minutes. All monitoring data and administered medications were documented on an anesthesia chart.

ESD procedure

All ESD procedures were performed in a dedicated endoscopy room. Three endoscopists participated: one highly experienced and certified by the Japan Gastroenterological Endoscopy Society, and two with less experience (having performed fewer than 50 ESD procedures on the digestive tract). The experienced endoscopist supervised the junior colleagues throughout the procedure.

A single-channel endoscope (GIFH260Z; Olympus Co., Tokyo, Japan) was used to identify and mark the lesion. Dissection was then performed using a device similar to a waterjet system (GIFQ260J; Olympus Co., Tokyo, Japan). The endoscopist used the tip of a dual knife to create small iodine dots approximately 2 mm from the lesion, marking the entire circumference. After marking, a solution of glycerol (Chugai Pharmaceutical Co., Tokyo, Japan) containing a small amount of indigo carmine was injected into the submucosa using a hypodermic needle (01862; Top Corporation, Tokyo, Japan). Finally, the submucosa was carefully separated from the muscularis mucosa, allowing for en-bloc resection.

Study endpoints

The primary endpoint was the frequency of involuntary body movements interfering with esophageal ESD using DEX and pethidine, whereas the secondary endpoint was the assessment of the safety of the sedation method. The frequency of hypotension, bradycardia, decreased SpO₂, and serious complications were also evaluated. Patient clinicopathological characteristics (age, sex, and alcohol consumption), endoscopic findings (lesion site), pathological findings based on ESD specimens (lesion depth, scar-related complications, and lesion size), and ESD outcomes (en bloc resection rate, R0 resection rate, sedation time, resection time, and procedural complications) were retrospectively collected. The total number of medications administered during ESD and monitoring data were collected from the anesthesia chart.

Definitions

Involuntary body movements that interfered with ESD were defined as constant movements necessitating physical restraint or prompting interruption of the procedure. Hypotension was defined as a systolic blood pressure ≤80 mmHg. Bradycardia was defined as a pulse rate below 40 beats per minute. Decreased SpO₂ refers to oxygen saturation falling below 90%. The presence of any of these conditions constituted worsening of vital signs.

Serious adverse events were defined as cardiopulmonary instability necessitating discontinuation of ESD. The endoscopist, sedation physician, and nurse discussed and determined whether an event constituted a serious adverse event during the procedure.

Lesion site and depth were classified according to the Japanese classification of esophageal cancer (20). En-bloc resection refers to the complete removal of the lesion in a single piece. R0 resection indicates that histopathological examination of the en-bloc resected tumor revealed no tumor cells at the margins. Resection time was defined as the time elapsed from the start of the mucosal incision to the removal of the resected specimen.

Bleeding complications encompassed two categories: intraoperative hemorrhage requiring blood transfusion and postoperative bleeding symptoms (hematemesis or hemorrhage) requiring endoscopic hemostasis. Perforation was defined as either the intraoperative endoscopic visualization of mesenteric fat or the presence of free air on postoperative computed tomography scan.

Statistical analysis

The Fisher’s exact test was used to compare categorical data. The Mann-Whitney U test was used to compare continuous data. Statistical significance was set at P<0.05.

Ethics

All procedures performed in this study were in accordance with the ethical standards of the institutional committee and with the Helsinki Declaration (as revised in 2013). The requirement for individual consent was waived for this retrospective study. No institutional review board (IRB) approval statement or ethics vote was obtained as the study was purely retrospective, data were anonymously used, and no harm may have been caused by inclusion in the study.

Results

Table 2 summarizes the clinicopathological characteristics of the study population. A total of 210 patients with 245 esophageal lesions were included. The majority of patients were male (80%), and alcohol consumption was reported in 83%. Notably, 99% of the lesions were resected en bloc, with no instances of bleeding or perforation observed during the procedures.

The average duration of DEX administration was 76 min, with an average procedure time of 65 min. Additionally, pethidine was administered to 40% of the patients at an average dose of 44 mg.

Primary outcome

One patient (0.5%) required discontinuation of treatment due to involuntary body movements that interfered with the procedure (Table 3). The patient had a history of multiple esophageal ESD procedures, resulting in a scarred resection area. Pain during the injection of glycerol solution into the scarred tissue triggered these movements, necessitating the discontinuation of ESD.

Secondary outcome

Thirty-three patients (15%) experienced worsening of vital signs during the procedure. This included hypotension, bradycardia, and decreased SpO₂. Hypotension occurred in 13 patients (6%) and resolved quickly with the administration of extracellular fluids without requiring hypertensive agents. Bradycardia was observed in 7 patients (3%) and treated with anticholinergic drugs. Lastly, decreased SpO₂ occurred in 13 patients (6%) and improved rapidly with supplemental oxygen alone, without needing airway interventions like nasal cannula or intubation (Table 3). Importantly, none of these vital sign changes resulted in serious complications, nor were there any issues related to prolonged drug effects after ESD completion.

We analyzed potential associations between worsening vital signs and age (80 years), duration of DEX administration (1 hour), alcohol consumption (280 g/week), and lesion location. However, no statistically significant associations were found (Table 4).

Discussion

This study demonstrates that the combination of DEX and pethidine as a sedation method during esophageal ESD effectively suppresses involuntary body movements that could hinder the procedure, enabling safe completion. Notably, no serious complications occurred, despite a few patients experiencing temporary vital sign changes.

This is the first study to report the use of DEX and pethidine for sedation during esophageal ESD. DEX is increasingly used in endoscopic procedures, and studies show significantly less patient movement compared to MDZ alone (17). While DEX has been used for esophageal ESD before, it was always combined with other sedatives (13,18). These studies relied on additional bolus doses of sedatives when sedation depth became insufficient. In contrast, our approach utilized a bolus dose of the analgesic pethidine to achieve the desired sedation level.

Body movement during endoscopic procedures can also arise from air insufflation causing abdominal distention and pharyngeal discomfort. In our study, pethidine administration effectively alleviated these symptoms. Previous studies reported minimal patient movement during ESD with DEX and propofol (95%) or DEX with MDZ and pethidine (97%) (13,18). Our findings mirrored these results, with 99.5% of patients experiencing no involuntary movements, suggesting the DEX-pethidine combination is equally effective in suppressing movement.

While DEX offers the advantage of sedation without significant respiratory depression, caution is warranted in using high doses or combining it with analgesics. In our study, 33 patients (15%) experienced temporary worsening of vital signs. However, these changes were not severe; SpO₂ depression readily resolved with oxygen administration, and no airway interventions were required.

DEX can inhibit the release of norepinephrine from sympathetic nerve endings, potentially leading to cardiovascular problems like hypotension or bradycardia due to weakened sympathetic nerve activity. This risk is particularly high in patients with pre-existing cardiac disease or the elderly (21). Studies have documented cases of DEX-induced cardiac arrest in patients with severe cardiac disease (22-25). Consequently, we excluded patients with a history of severe cardiac disease from this study. Additionally, decreased cardiac output can elevate plasma DEX concentrations (26), suggesting a dose-dependent risk of cardiovascular events (27). The administration of 1 L of extracellular fluid before treatment in our study may have helped prevent vital sign deterioration in vulnerable elderly patients by addressing potential dehydration. Even with longer DEX administration times and higher doses, fluid replacement strategies may contribute to maintaining stable vital signs.

This study has several limitations. First, it was a retrospective, observation study conducted in a single center with a single treatment arm. Retrospective data collection carries the risk of missed complications, body movements, and selection bias, potentially inflating the efficacy results. Second, the lack of a limit on pethidine doses may have influenced the results. While subjectivity is inherent in the additional administration of pethidine, we believe the ability to manage sedation with defined criteria in our study is a valuable finding with potential for reproducibility. Third, patient satisfaction with the sedation method was not assessed. While sedation depth was monitored and medication adjusted accordingly, this low-sedation protocol may not provide amnesia. Evaluating patient comfort with this protocol after treatment would be beneficial. Further evaluation of these findings requires multicenter, prospective clinical trials with larger sample sizes.

Conclusions

The combination of DEX and pethidine offers an effective sedation option for esophageal ESD, provided careful attention is paid to medical history and potential fluctuations in vital signs.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-7/rc

Data Sharing Statement: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-7/dss

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-7/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-7/coif). T.I. serves as an unpaid editorial board member of Annals of Esophagus from May 2022 to April 2024. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional committee and with the Helsinki Declaration (as revised in 2013). The requirement for individual consent was waived for this retrospective study. No IRB approval statement or ethics vote was obtained as the study was purely retrospective, data were anonymously used, and no harm may have been caused by inclusion in the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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