https://orcid.org/0009-0003-9455-4652
Figures
Abstract
Background
Cardio-biliary reflex can lead to cardiac arrest, brady-arrhythmia, cardiogenic shock, and other severe complications. NMDA receptor antagonists have been shown to have the effect of anti-vagal reflex. However, the regulation of vagus reflex by esketamine, an NMDA receptor antagonist, remains unclear. Our study aims to investigate intravenous low-dose esketamine on cardio-biliary reflex.
Methods
In this randomized controlled trial, adult patients undergoing laparoscopic cholecystectomy were allocated in a 1:1 ratio to esketamine group or control group. 5 minutes before surgical incision, participants in the esketamine group received 0.3 mg/kg of esketamine, while the control group received an equivalent volume of normal saline. The primary outcome was the occurrence of cardio-biliary reflex. Postoperative pain was assessed using the Visual Analogue Scale (VAS) on days 1, 2, and 3 post-surgery.
Results
Our final analysis included 140 participants. The incidence of the cardio-biliary reflex occurred in 15 patients (21.4%) in the control group compared with 6 patients (8.6%) in the esketamine group (relative risk 0.34; 95%confidence interval (95% CI): 0.125–0.947; P < 0.05). Patients in the esketamine group reported lower pain intensity with movement on postoperative days (POD)1, 2, and 3 with mean differences (MD) of 0.59, 0.70, and 0.47 points respectively (all P < 0.05). Additionally, pain intensity at rest was also lower in the esketamine group at all observation time points (POD1: MD 0.51, POD2: MD 0.40, POD3: MD 0.30, all P < 0.05).
Citation: Zhang X, Duan P, Sun Y, Na Q (2025) Effect of low-dose esketamine on cardio-biliary reflex and postoperative pain during laparoscopic cholecystectomy surgery: A randomized, controlled trail. PLoS One 20(5): e0321892. https://doi.org/10.1371/journal.pone.0321892
Editor: Dereje Zewdu Assefa, Monash University, ETHIOPIA
Received: September 12, 2024; Accepted: March 6, 2025; Published: June 2, 2025
Copyright: © 2025 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The original data in this study consist of the data obtained from a questionnaire survey conducted at a tertiary hospital in China. Respondents were informed that the results would be presented anonymously. These data are regarded as identifiable personal data under the General Data Protection Regulation (GDPR), thus they cannot be publicly shared. All relevant data shared in the paper have been de-identified. Interested researchers may contact the the Ethics Review Office (zssl188@sina.com) with data access requests.
Funding: Our research is supported by National Science of Liaoning Province(2020-MS-041) and Applied Basic Research Project of Liaoning Province (2023JH2/101300075) from Yingjie Sun. Research Projects of Xiang yang Central Hospital (2024YJ07B) is supported by Xiaodong Zhang. Qi Na analyzed the data and revised the manuscript. Corresponding author QI NA analyzed the data, revised the manuscript and submitted the paper, and he did not provide a grant funder.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Laparoscopic cholecystectomy (LC) surgery has emerged as the gold standard for treating symptomatic cholelithiasis, acute cholecystitis, and other gallbladder diseases. In the US, gallbladder disease impacts approximately 20 million individuals, significantly increasing familial economic burdens [1,2]. After laparoscopic surgery, some complications are still unavoidable. Commonly reported issues include nausea, vomiting, biliary reflex, abdominal pain, and surgical infection [3,4]. Of particular concern is the cardio-biliary reflex, a prevalent vagus nerve reflex that can lead to cardiac arrest, arrhythmia, cardiogenic shock, and other severe complications. The vagus reflex is mediated by the trigeminal nerve (afferent limb) and the vagus nerve (efferent limb). During LC, manipulation of the gallbladder can activate the vagus nerve, triggering adverse cardiac events such as sinus bradycardia, arrhythmia, and asystole. Therefore, devising effective strategies to prevent cardio-biliary reflex is crucial for the safety of both surgery and anesthesia.
Another significant challenge following LC surgery is post-operative pain, which causes anxiety, depression, insomnia, and can prolong hospital stays, inflate medical costs, and hinder early postoperative recovery [5]. Inadequate pain management post-LC can increase risk of developing persistent post-surgery pain [6,7]. While opioids are commonly used for post-surgical pain management, their adverse complications-tolerance, addiction, nausea, vomiting, respiratory depression, and hyperalgesia-necessitate alternatives. Non-opioid analgesics are increasingly recognized as vital components of multimodal analgesia reducing opioid-related side effects [8]. Esketamine, a potent N-methyl-D-aspartate (NMDA) receptor antagonist, has shown a promise in reducing pain intensity and opioid requirements post-surgery [9]. NMDA receptors modulate spinal neuronal activity, influence wind-up and central sensitization of dorsal horn sensory neurons, and are crucial in the development of pain states [10]. Vagus nerve excitation increases gallbladder motility and its effect can be abolished by administering NMDA recptors [10]. Esketamine is the dextral form of ketamine and has a higher affinity for NMDA recptor. Our study aims to investigate whether intravenous low-dose esketamine administered before skin incision can effectively reduce the incidence of cardio-biliary reflex and alleviate postoperative pain in patients undergoing LC.
Methods
This randomized, double-blind, placebo-controlled trial was conducted at Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China, from January 15, 2024, to April 15, 2024. The study protocol received approval from the Hospital Research Ethics Committee (Ethical approval No.2023-113-02) and conformed to the Declaration of Helsinki and CONSORT guidelines. The trial was registered at the Chinese Clinical Trial Registry (January 02, 2024; ChiCTR2400079362; https://www.chictr.org.cn/). Written or verbal consent from all participants.
Inclusion and exclusion criteria
A total of 148 patients aged 18–60 years, and who were scheduled for elective LC with American Society of Anesthesiologists (ASA) grade I to III was enrolled to participate in this trial. Exclusion criteria included: patients were contraindication to esketamine (e.g., allergic to esketamine and any schizophrenia, mania, and any other mental illness); pathological sinus node syndrome; heart rate < 45 beats/min; mental, language or communication barrier; converted to open surgery; contraindications to anesthetic drugs (remifentanil, sufentanil, propofol). Patients participating in another study within 4 weeks before enrollment were also excluded.
Randomization and double-blind
A biostatistician uses a computer-generated list of random numbers in a 1:1 ratio. Each participant is assigned a unique random number; participants are then ranked in ascending or descending order based on these random numbers. According to pre-established sample sizes for each treatment group, subjects are selected sequentially by their random number to be allocated to the respective treatment arms. Based on the random seeds, patients were allocated into two groups: esketamine group (0.3 mg/kg of esketamine, Jiangsu hengrui Pharmaceutical Co., Ltd.) or control group (same volume of normal saline). The randomization sequence was sealed in numbered opaque envelopes managed by a research coordinator, who was not involved in anesthesia management, perioperative care, or postoperative follow-up. During the study period, the research coordinator open envelope before anesthesia induction and prepared the study drugs according to group assignment. The study drugs stored the drugs with identical appearance sterile syringes produced by the same manufacturer. Blinding was maintained for patients, anesthesiologists, surgeons, and investigators. Furthermore, all surgeries were performed by same surgeries and anesthesiologists’ team.
Anaesthesia, perioperative and intraoperative care
Preoperative anesthesia evaluation occurred one day before surgery. Standard fasting guidelines were followed. After patients enter to the operating room, electrocardiogram, heart rate, peripheral pulse oxygen saturation, non-invasive blood pressure, and nasopharyngeal temperature was routinely monitored. Ringer lactate (5 mL/kg) infusion via venous access was achieved by peripheral intravenous catheter. The participants routinely inhaled oxygen at 3 L/min through a nasal catheter. General anaesthesia was induced with sufentanil (0.4 µg/kg), etomidate (0.2 mg/kg), rocuronium (0.9 mg/kg). Endotracheal intubation was performed by the same anesthetist, and mechanical ventilation was used to maintain PetCO2 in the range of 35–45 mmHg. Awake fiberoptic bronchoscopy tracheal intubation was performed for those subjects with predicted difficult airway. After tracheal intubation, an anesthesia nurse took trail drugs from trial coordinator and intravenous administration of it. Anesthesia was maintained with propofol (60–120 µg/kg/min), remifentanil (0.2–0.5 µg/kg/min), and sevoflurane (1–2%). Anaesthesia depth was targeted to maintain BIS between 40 and 60 by increasing or decreasing intravenous propofol, or sufentail. Intraoperative noninvasive mean blood pressure was maintained within 20% of the baseline values and above 60 mmHg, which was achieved by intravenous infusion of phenylephrine or nitroglycerin (20 µg increments or continuous infusion). Severe bradycardia was defined as intraoperative patient’s heart rate < 45 beats/ min, and 0.25 mg atropine was administrated by peripheral intravenous catheter. After surgery, all of the subjects were transferred to the post-anaesthesia care unit (PACU) for recovery before returning to the ward. After the surgery, patients were administered intravenous flurbiprofen axetil 50mg, and a bilateral transversus abdominis plane block was performed under ultrasound guidance, with each side receiving 20mL of 0.375% ropivacaine.
Data collection and measurements
The baseline clinical characteristics of all the patients were collected: age, weight, height, smoking habits, drinking, allergies, chronic pain, marital status, education, history of disease, ASA status. Non-invasive blood pressure, heart rate, respiratory rate and pulse oxygen saturation was recorded at baseline (T0), immediately before esketamine or normal saline injection (T1), 5 minutes after esketamine or normal saline injection (T2), immediately before pulling the gallbladder (T3), 5min after pulling the gallbladder (T4), immediately after end of operation (T5), immediately upon awakening (T6). Various intraoperative parameters noted included: duration of surgery and anaesthesia, mechanical ventilation time, extubation time, infusion volume, estimated blood loss.
The primary outcome was the incidence of cardio-biliary reflex which is defined by a decrease in heart rate and blood pressure by greater than 20% following traction of the gallbladder. The cardio-biliary reflex also mimics the special ECG changes of acute coronary syndrome, such as ST-segment elevation and T-wave inversion. The reflex most commonly results in sinus bradycardia. Furthermore, it also has a reported association with reduced arterial pressure, arrhythmia, asystole, and even cardiac arrest. Atropine or epinephrine was used to maintain heart rate within 20% of its baseline in each time.
Mini-mental state examination (MMSE) and hospital anxiety and depression scale (HAD) assess patient’s anxiety, depression and cognitive function before and 1 day after surgery [11]. Post-operative pain intensity at rest and during movement was evaluated with visual analogue scale (VAS) pain score on postoperative day 1, 2, and 3 [12]. If the patient’s pain score was more than 3 points or requiring analgesic drugs, a low-dose (2–3ug/kg) sufentanil would be given. In addition, the number of patients who requested extra rescue pain treatment during the postoperative analgesia was also recorded. Adverse events including nausea, vomiting, dizziness, increased salivation, delirium, drowsiness, and pruritus were recorded after recovery from anesthesia and on the first day after surgery.
Statistical analysis
The sample size calculation used PASS 11.0 software (NCSS, LLC. Kaysville, Utah). According to our preliminary observations, the incidence of cardio-biliary reflex in control group was about 27%. Sample size calculation was based on an anticipated r incidence of 6% in the esketamine group, with a 2-sided alpha error of 0.05 and 90% power. Considering a 20% dropout rate, a total of 148 subjects were planned for enrollment. Data are expressed as mean ± SD, median(inter-quartile range) or absolute numbers. Categorical variables were analysed with χ2 tests, continuity correction χ2 tests, or Fisher’s exact tests; between-group differences were expressed as relative risks (RR) and 95% CI. Continuous variables with normal distribution were analyzed with independent-sample t-tests and Linear Mixed-Effects Models; between-group differences were expressed as mean difference (MD) and 95% CI. Those with non-normal were analyzed with Manne-Whitney U tests. 2-way ANOVA with Bonferroni post hoc test was employed for pain and intraoperative data comparisons. Statistical analyses were using the GraphPad Prism (GraphPad Prism 8.3.0, San Diego, CA) and SPSS 25.0 (IBM, Armonk, NY, USA).
Result
Baseline characteristics
148 patients were initially assessed for participation in our study. Finally,140 eligible patients were randomized to esketamine group (n = 70) or control group (n = 70, Fig 1). 8 patients were excluded from this study: 3 did not satisfy the inclusion criteria, 2 patients declined to participate our study, 1 patient refused surgery, 1 patient was excluded due to sinus bradycardia, 1 patient was excluded on account of chronic heart failure (Fig 1). A comparative analysis of demographic and clinical characteristics exhibited no significant difference across two groups (P > 0.05, Table 1).
Intraoperative medical indicators
Intraoperative administration esketamine decreased in the incidence of gallbladder-heart reflexes compared to the control group [control group vs. esketamine group; 21.4% (15/70) vs 8.6% (6/70), relative risk (RR) 0.34; 95% confidence interval (95% CI): 0.125–0.947; P < 0.033]. Intraoperative parameters, including duration of anaesthesia and surgery, the times of mechanical ventilation, extubation and recovery, infusion volume, and estimated blood loss, were well balanced across groups (P > 0.05, Table 2). Blood pressure values and heart beats were significantly higher in the esketamine group at 5 minutes after esketamine injection and 5min after pulling the gallbladder (P < 0.05, Fig 2A, B, C, D). At other monitored timepoints, there were no significant differences in blood pressure and heart rate between the two groups (P > 0.05, Fig 2A, B, C, D). At any time point during the operation, no statistical difference was observed in the fluctuation of respiratory rate and pulse oxygen saturation between the 2 groups (P > 0.05, Fig 2E, F).
Note: T0: baseline; T1: immediately before esketamine or normal saline injection; T2:5 minutes after esketamine or normal saline injection; T3: immediately before pulling the gallbladder; T4: 5min after pulling the gallbladder; T5: immediately after end of operation; T6: immediately upon awakening. *P < 0.05 vs. the control group.
Comparison of postoperative VAS score
Better analgesic effect was achieved in esketamine group rather than that in the control group. Patients in the esketamine group experienced a significantly lower pain intensity with movement compared to the control group on postoperative days 1, 2, and 3 [i.e., POD 1: control group vs. esketamine group, mean difference (MD) 0.59 points, 95% CI 0.17–1.0; POD 2: MD 0.70 points, 95% CI 0.22–1.18; POD 3: MD 0.47 points, 95% CI 0.06–0.88); all P < 0.05, Fig 3A]. At observation time points, pain intensity at rest was lower in the esketamine group than in the control [i.e., POD 1: control group vs. esketamine group, MD 0.51 points, 95% CI 0.18–0.85; POD 2: MD 0.40 points, 95% CI 0.02–0.78; POD3: MD 0.30 points, 95% CI 0.04–0.56; all P < 0.05, Fig 3B].
Note: POD1: postoperative day 1; POD2: postoperative day 2; POD3: postoperative day 3.
Comparison of H3AD and MMSE score
The Preoperative HAD and MMSE score did not differ between the two groups (P > 0.05, Table 3). The HAD-A and HAD-D score was lower in the esketamine group compared to the control group at POD1 (P < 0.05, Table 3). The differences were no clinically significant, as all the patients’ scores were lower than seven points, indicating that the patients were free of anxiety and depression. There was no significant difference in MMSE between the two groups at POD1 (P > 0.05, Table 3).
Comparison of complications and analgesics requirements between two groups
There were no statistically significant differences in the incidence of nausea, vomiting, dizziness, recovery time, glandular secretion rate, and the number of patients requiring analgesia between the two groups (P > 0.05, Table 4). Both groups demonstrated similar frequencies of drowsiness and pruritus, with no significant differences observed (P > 0.05, Table 4). Importantly, there were no reported cases of psychiatric symptoms in any of the patients during the study period. Fewer subjects in the esketamine group asked for supplemental analgesics than in the control group [17.1% (12/70) vs. 7.1% (5/70); relative risk 1.50, 95% CI 1.05–2.14, P < 0.05, Table 4].
Discussion
In this study, we evaluated the effects of intraoperative single low-dose esketamine on cardio-biliary reflex and postoperative pain. Results demonstrated that low-dose esketamine significantly reduced the occurrence of cardio-biliary reflex and post-surgery pain and the requirement for supplemental analgesics within 72 h, without increasing adverse events, including nausea, vomiting, dizzy, psychiatric symptoms and others.
The cardio-biliary reflex, characterized by reflex sinus bradycardia and other electrocardiogram changes during acute cholecystitis or biliary colic, has been a major concern in such surgeries. In 1971, O’Reilly and Krauthamer firstly described the development of reflex sinus bradycardia and other various electrocardiogram changes in the setting of acute cholecystitis or biliary colic, known as Cope’s sign or the cardio-biliary reflex [13,14]. This reflex is incited by acute cholecystitis pain of the gallbladder, which leads to increased activation of autonomic neurons in the reflex arc inducing heart-related adverse events [15,16]. During LC, the surgeon manipulates the gallbladder can activate the vagus nerve inducing cardio-biliary reflex. Previous studies have demonstrated that presynaptic N-methyl-D-aspartate (NMDA) receptors expressed on vagal afferent terminals are involved in regulating vagal afferent activity [17]. Our study showed that a single dose of esketamine could effectively reducing the incidence of this reflex. This aligns with prior research highlighting the role of NMDA receptors in regulating vagal afferent activity [17]. Nonselective NMDA receptor antagonists inhibit vagus signaling by modulating various ion channels [17]. Ketamine has been shown to inhibit vagus-induced oculocardiac reflexes by excitating the sympathetic nerve [18]. Esketamine may inhibit vagal reflexes by the same mechanism. The specific reason may be that esketamine’s ability to deepen anesthesia and modulate vagal responses could be key to mitigating this reflex. The specific mechanism by which esketamine inhibits vagal reflex during cholecystectomy needs to be confirmed by further animal or clinical studies.
Small doses of esketamine has been shown to be beneficial in maintaining hemodynamic stability during LC [19]. In our study, we observed that blood pressure values and heart beats were higher in the esketamine group than that in the normal saline group at 5 minutes after esketamine injection and 5min after pulling the gallbladder. Currently, multicenter, double-blind randomized clinical trial of 903 women who were administered 0.25 mg/kg esketamine or saline before incision showed that the mean arterial pressure and heart rate were higher in the esketamine group than in the control group at 5 minutes after study drug administration [20]. Esketamine may stimulate the sympathetic nervous system to increase blood pressure and heart rate, especially when given in high doses [21]. In Zhang et al. ‘s study, a single intravenous injection of 0.15 mg/kg of esketamine was associated with a reduced risk of hypotension during cesarean section under spinal anesthesia with ropivacaine at 12 mg [22]. The reason for this may be due to esketamine exerts sympathetic excitatory effect that counteracted the cardiovascular inhibitory effect of anesthetic drugs, adverse reflexes [23]. The sympathetic excitatory effect of esketamine is related to two aspects:1) Esketamine blocks the sodium channel of brain stem parasympathetic neurons and inhibits parasympathetic nerve activity; 2) Esketamine inhibits NO release and enhances sympathetic nerve activity [24].
Severe acute postoperative pain often occurs in patients undergoing abdominal surgery [25]. Laparoscopic cholecystectomy is a minimally invasive procedure, but many patients still complain of moderate to severe pain-surgery [26]. Although non-opioid medications and regional/neuraxial techniques have been propose to improve analgesia, postoperative analgesia remains suboptimal [27]. Previous studies have shown that esketamine is effective in reducing pain intensity in the rest and movement in the short period after surgery [28]. In our study, intravenous administration of esketamine 5 minutes before the surgical incision effectively improved postoperative pain. Ktamine (bolus 0.2 mg/kg over 30 min followed by 0.12 mg/ kg/h for 24 h)) decreases pain intensity and opioid requirements following spinal fusion surgery in opioid-tolerant patients [29]. In addition, A recent meta-analysis of 30 randomized controlled trials, including 1,865 patients undergoing elective spinal surgery, showed that perioperative low doses of ketamine reduced pain intensity and opioid consumption at 12, 24, and 48 hours, with no increase in adverse events [30]. In this study, low doses of esketamine reduced post-operative static and dynamic pain 72 h postoperatively. Clinically significant difference was also observed in reducing the requirement for opioids. Esketamine is an NMDA receptor inhibitor, which can inhibit hyperalgesia and prolong postoperative analgesia [31,32]. Prior research has shown that preemptive low-doses ketamine can provide an adequate postoperative analgesia and increases the analgesic effect of tramadol following laparoscopic cholecystectomy [33].
Anxiety and depression often occur in surgical patients, which has become a worldwide public health problem [34]. Due to patients’ worries about the results of surgery, patients usually experience serious anxiety and depression. Effective measures to prevent anxiety and depression during perioperative period are conducive to rapid recovery after surgery. The FDA updated the approval of intranasal esketamine can improve adults with major depression and suicidal ideation and behavior [35]. In addition, the results of a systematic review and data analysis of 2,903 patients indicate that ketamine and esketamine are effective and safe for the treatment of patients with depression [36]. Low doses of ketamine and esketamine have been reported to be effective in alleviating postpartum depression [22,37]. However, in our results showed that low-doses of esketamine statistically reduced HAD scores, but our study found no significant clinical difference in these aspects, possibly due to the young patient demographic and small sample size.
Low-dose ketamine infusion is recommended to improve postoperative analgesia [38]. However, low-dose ketamine still produce side-effects, including psychiatric symptoms [39]. However, our findings confirm that the use of low doses esketamine in patients undergoing laparoscopic cholecystectomy is safe and does not increase the risk of psychiatric symptoms. A single intravenous injection of esketamine increased glandular secretion in patients undergoing thyroidectomy, and their results were consistent with the findings of this study [40]. No significant difference was found in the incidence of nausea, vomiting, dizzy, drowsiness and other complications in our study. The side effects of low doses of esketamine need to be further evaluated in large, multi-center studies.
Limitation
Firstly, the relatively small sample size may not fully underpowered to detect the side effects of esketamine. Second, we only tested the effects of a fixed dose of esketamine (0.3 mg/kg). Fourth, more comprehensive investigations into biomarkers of the cardio-biliary reflex and rapid ECG changes associated with this reflex are warranted. Thirdly, we included a small number of elderly patients, and did not conduct subgroup analysis by age, so it is necessary to further explore the occurrence of outcomes at different ages.
Conclusion
In conclusion, intraoperative low-dose esketamine effectively reduces the occurrence of cardio-biliary reflex and postoperative pain in patients undergoing laparoscopic cholecystectomy. Moreover, it stabilizes intraoperative circulation without increasing adverse complications. The current findings are only confirmed the effectiveness of intravenous low-dose esketamine of Chinese population.
References
- 1. Gutt C, Schläfer S, Lammert F. The Treatment of Gallstone Disease. Dtsch Arztebl Int. 2020;117(9):148–58. pmid:32234195
- 2. Gallaher JR, Charles A. Acute Cholecystitis: A Review. JAMA. 2022;327(10):965–75. pmid:35258527
- 3. Muñoz Leija MA, Alemán-Jiménez MC, Plata-Álvarez H, Cárdenas-Salas VD, Valdez-López R. Laparoscopic Management of Cholecystoduodenal and Cholecystocolic Fistula: A Clinical Case Report. Cureus. 2023;15(6):e40657. pmid:37476135
- 4. Chávez KV, Márquez-González H, Aguirre I, Orellana JC. Prognostic risk factors for conversion in laparoscopic cholecystectomy. Updates Surg. 2018;70(1):67–72. pmid:28980164
- 5. Barazanchi AWH, MacFater WS, Rahiri J-L, Tutone S, Hill AG, Joshi GP, et al. Evidence-based management of pain after laparoscopic cholecystectomy: a PROSPECT review update. Br J Anaesth. 2018;121(4):787–803. pmid:30236241
- 6. Zhang Y, Wang Y, Zhang X. Effect of pre-emptive pregabalin on pain management in patients undergoing laparoscopic cholecystectomy: A systematic review and meta-analysis. Int J Surg. 2017;44:122–7. pmid:28642088
- 7. Medina-Diaz-Cortés G, Brancaccio-Pérez IV, Esparza-Estrada I, Barbosa-Camacho FJ, Fuentes-Orozco C, González-Hernández PG, et al. Differences in Postoperative Pain, Nausea, and Vomiting After Elective Laparoscopic Cholecystectomy in Premenopausal and Postmenopausal Mexican Women. World J Surg. 2022;46(2):356–61. pmid:34731260
- 8. Tochie JN, Bengono Bengono RS, Metogo JM, Ndikontar R, Ngouatna S, Ntock FN, et al. The efficacy and safety of an adapted opioid-free anesthesia regimen versus conventional general anesthesia in gynecological surgery for low-resource settings: a randomized pilot study. BMC Anesthesiol. 2022;22(1):325. pmid:36280804
- 9. Qiu D, Wang X-M, Yang J-J, Chen S, Yue C-B, Hashimoto K, et al. Effect of Intraoperative Esketamine Infusion on Postoperative Sleep Disturbance After Gynecological Laparoscopy: A Randomized Clinical Trial. JAMA Netw Open. 2022;5(12):e2244514. pmid:36454569
- 10. Shin H-J, Na H-S, Do S-H. Magnesium and Pain. Nutrients. 2020;12(8):2184. pmid:32718032
- 11. Philippot A, Dubois V, Lambrechts K, Grogna D, Robert A, Jonckheer U, et al. Impact of physical exercise on depression and anxiety in adolescent inpatients: A randomized controlled trial. J Affect Disord. 2022;301:145–53. pmid:35007642
- 12. Klotz R, Seide SE, Knebel P, Probst P, Bruckner T, Motsch J, et al. Continuous wound infiltration versus epidural analgesia for midline abdominal incisions - a randomized-controlled pilot trial (Painless-Pilot trial; DRKS Number: DRKS00008023). PLoS One. 2020;15(3):e0229898. pmid:32142529
- 13. Cope Z. A sign of gall-bladder disease. Br Med J. 1970;3(5715):147–8. pmid:5431086
- 14. O’Reilly MV, Krauthamer MJ. “Cope’s sign” and reflex bradycardia in two patients with cholecystitis. Br Med J. 1971;2(5754):146. pmid:5581494
- 15. Fang S, Gao L, Yang F, Gong Y-J. Delayed reversibility of complete atrioventricular block: cardio-biliary reflex after alcohol septal ablation in a patient with hypertrophic obstructive cardiomyopathy. BMC Cardiovasc Disord. 2021;21(1):372. pmid:34344308
- 16. Mainali A, Adhikari S, Chowdhury T, Shankar M, Gousy N, Dufresne A. Symptomatic Sinus Bradycardia in a Patient With Acute Calculous Cholecystitis Due to the Cardio-Biliary Reflex (Cope’s Sign): A Case Report. Cureus. 2022;14(6):e25585. pmid:35785008
- 17. Vance KM, Rogers RC, Hermann GE. NMDA receptors control vagal afferent excitability in the nucleus of the solitary tract. Brain Res. 2015;1595:84–91. pmid:25446446
- 18. Oh JN, Lee SY, Lee JH, Choi SR, Chin YJ. Effect of ketamine and midazolam on oculocardiac reflex in pediatric strabismus surgery. Korean J Anesthesiol. 2013;64(6):500–4. pmid:23814649
- 19. Wang D, Song Z, Zhang C, Chen P. Bispectral index monitoring of the clinical effects of propofol closed-loop target-controlled infusion: Systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2021;100(4):e23930. pmid:33530193
- 20. Xu L-L, Wang C, Deng C-M, Dai S-B, Zhou Q, Peng Y-B, et al. Efficacy and Safety of Esketamine for Supplemental Analgesia During Elective Cesarean Delivery: A Randomized Clinical Trial. JAMA Netw Open. 2023;6(4):e239321. pmid:37083664
- 21. Adams HA, Meyer P, Stoppa A, Müller-Goch A, Bayer P, Hecker H. Anaesthesia for caesarean section. Comparison of two general anaesthetic regimens and spinal anaesthesia. Anaesthesist. 2003;52(1):23–32. pmid:12577162
- 22. Zhang X, Wang J, An X-H, Chao Y-C, Bian Y, Xu Z, et al. Optimum dose of spinal ropivacaine with or without single intravenous bolus of S-ketamine during elective cesarean delivery: a randomized, double-blind, sequential dose-finding study. BMC Pregnancy Childbirth. 2021;21(1):746. pmid:34736438
- 23. Qian XL, Li P, Chen YJ, Xu SQ, Wang X, Feng SW. Opioid Free Total Intravenous Anesthesia With Dexmedetomidine-Esketamine-Lidocaine for Patients Undergoing Lumpectomy. J Clin Med Res. 2023;15(8–9):415–22. pmid:37822850
- 24. Zhou J-S, Peng G-F, Liang W-D, Chen Z, Liu Y-Y, Wang B-Y, et al. Recent advances in the study of anesthesia-and analgesia-related mechanisms of S-ketamine. Front Pharmacol. 2023;14:1228895. pmid:37781698
- 25. Casas-Arroyave FD, Osorno-Upegui SC, Zamudio-Burbano MA. Therapeutic efficacy of intravenous lidocaine infusion compared with thoracic epidural analgesia in major abdominal surgery: a noninferiority randomised clinical trial. Br J Anaesth. 2023;131(5):947–54. pmid:37758623
- 26. Yang X, Zhang Y, Chen Y, Xu M, Lei X, Fu Q. Analgesic effect of erector spinae plane block in adults undergoing laparoscopic cholecystectomy: a systematic review and meta-analysis of randomized controlled trials. BMC Anesthesiol. 2023;23(1):7. pmid:36609244
- 27. Zhang Y, Cui F, Ma J-H, Wang D-X. Mini-dose esketamine-dexmedetomidine combination to supplement analgesia for patients after scoliosis correction surgery: a double-blind randomised trial. Br J Anaesth. 2023;131(2):385–96. pmid:37302963
- 28. Wang X, Lin C, Lan L, Liu J. Perioperative intravenous S-ketamine for acute postoperative pain in adults: A systematic review and meta-analysis. J Clin Anesth. 2021;68:110071. pmid:33007645
- 29. Boenigk K, Echevarria GC, Nisimov E, von Bergen Granell AE, Cuff GE, Wang J, et al. Low-dose ketamine infusion reduces postoperative hydromorphone requirements in opioid-tolerant patients following spinal fusion: A randomised controlled trial. Eur J Anaesthesiol. 2019;36(1):8–15. pmid:30113350
- 30. Zhou L, Yang H, Hai Y, Cheng Y. Perioperative Low-Dose Ketamine for Postoperative Pain Management in Spine Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pain Res Manag. 2022;2022:1507097. pmid:35401887
- 31. Shen J, Song C, Lu X, Wen Y, Song S, Yu J, et al. The effect of low-dose esketamine on pain and post-partum depression after cesarean section: A prospective, randomized, double-blind clinical trial. Front Psychiatry. 2022;13:1038379. pmid:36683972
- 32. Song X, Wang F, Dong R, Zhu K, Wang C. Efficacy and Safety of Remimazolam Tosilate Combined With Esketamine for Analgesic Sedation in Mechanically Ventilated ICU Patients: A Single-Arm Clinical Study Protocol. Front Med (Lausanne). 2022;9:832105. pmid:35372406
- 33. Launo C, Bassi C, Spagnolo L, Badano S, Ricci C, Lizzi A, et al. Preemptive ketamine during general anesthesia for postoperative analgesia in patients undergoing laparoscopic cholecystectomy. Minerva Anestesiol. 2004;70(10):727–34; 734–8. pmid:15516884
- 34. Mirani SH, Areja D, Gilani SS, Tahir A, Pathan M, Bhatti S. Frequency of Depression and Anxiety Symptoms in Surgical Hospitalized Patients. Cureus. 2019;11(2):e4141. pmid:31058024
- 35. Reif A, Bitter I, Buyze J, Cebulla K, Frey R, Fu D-J, et al. Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. N Engl J Med. 2023;389(14):1298–309. pmid:37792613
- 36. Bahji A, Zarate CA, Vazquez GH. Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. Expert Opin Drug Saf. 2022;21(6):853–66. pmid:35231204
- 37. Yao J, Song T, Zhang Y, Guo N, Zhao P. Intraoperative ketamine for reduction in postpartum depressive symptoms after cesarean delivery: A double-blind, randomized clinical trial. Brain Behav. 2020;10(9):e01715. pmid:32812388
- 38. Schwenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, Narouze S, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):456–66. pmid:29870457
- 39. Gil LV, Mazzeffi MA, Cai Y, McLeod WW, Porter SB. Reasons for discontinuation of acute postoperative pain ketamine infusions: A retrospective case-control study. Pain Pract. 2021;21(7):759–65. pmid:33811788
- 40. Ren Y-L, Yuan J-J, Xing F, Zhu L-N, Zhang W. Effects of Different Doses of Esketamine on Pain Sensitivity of Patients Undergoing Thyroidectomy: A Randomized Controlled Trial. Pain Ther. 2023;12(3):739–50. pmid:36933139