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Background: Benzodiazepines reduce postoperative nausea and vomiting (PONV); however, conflicting results have been reported regarding the use of remimazolam, a novel benzodiazepine., Objective: This meta-analysis examines whether remimazolam reduces PONV incidence compared with propofol or volatile agents used in general anesthesia., Material and Methods: Electronic databases, including PubMed, EMBASE, CENTRAL, and Web of Science, were searched on 31 July 2023. The primary outcome was the incidence of PONV. Secondary outcomes included PONV severity, rescue antiemetic use, amounts of remifentanil used, and participant satisfaction scores. Odds ratios (OR) and mean differences (MD) with 95% confidence intervals (CI) were calculated using a random-effects model. The risk of bias (RoB) was assessed using the Cochrane RoB2 tool., Results: A total of 1514 adult patients from 11 randomized controlled trials were included. The incidences of PONV in the remimazolam and control groups were 16.1% and 16.5%, respectively. Remimazolam did not increase the incidence of PONV (OR 0.62; 95% CI, 0.37-1.04; p = 0.0676; I 2  = 48%). Subgroup analysis showed a significant reduction in PONV with remimazolam vs. volatile agents (OR 0.25; 95% CI, 0.13-0.47; P = 0.0000; I 2  = 0%) but not vs. propofol (OR 1.04; 95% CI, 0.70-1.56; p = 0.8332; I 2  = 0%). More remifentanil was used in the remimazolam group vs. the volatile group, with no significant difference between remimazolam and propofol groups. Participant satisfaction scores were higher with remimazolam., Conclusion: Remimazolam did not increase PONV risk compared to propofol and reduced PONV incidence compared to volatile agents, with higher participant satisfaction. To validate the present findings, further well-planned large clinical trials are required., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objective: In this study, we investigated the safety and practicability of ultra-fast track anesthesia (UFTA) for endoscopic thoracic sympathectomy (ETS)., Methods: A total of 72 patients with palmar hyperhidrosis undergoing ETS were randomly divided into three groups: the UFTA group (group I), the group undergoing single-lumen tracheal intubation with local infiltration anesthesia technique (group II), and the group undergoing single-lumen tracheal intubation with routine anesthesia (group III). Mean arterial pressure (MAP) and heart rate (HR) were recorded for all three groups at the following six time points: Before anesthetics administration (T0), the time of intubating or inserting laryngeal mask airway (T1), the time of incising skin (T2), the time of disconnecting of the right sympathetic nerve (T3), the time of disconnecting of the left sympathetic nerve (T4), the time of withdrawing the tracheal tube or laryngeal mask airway (T5), and the time of transferring the patient to a post-anesthesia care unit (PACU) (T6). The three groups were compared from the following perspectives: surgery duration; anesthesia recovery duration, that is, the duration from discontinuation of anesthesia to extubating the tracheal tube; the dose of propofol and remifentanil per kilogram body mass per unit time interval (the time at the end of the procedure, which lasted from anesthesia induction to incision suturing); and the visual analog scale (VAS) in the resting state in the PACU., Results: Based on pairwise comparisons, the average HR and average MAP values of the three groups differed significantly from T2 to T6 (p < 0.05). As demonstrated by the correlation analysis between remifentanil and propofol with HR and MAP, the doses of the total amount of remifentanil and propofol were lower, and group I used less remifentanil and propofol than group II. No patient in group I experienced throat discomfort following surgery. Patients in groups II and III experienced a range of postoperative discomfort. The VAS scores of groups I and II were significantly lower than those of group III, with group I lower than group II., Conclusion: When utilized in ETS, UFTA can provide effective anesthesia for minor traumas. It is safe, effective, and consistent with the enhanced recovery philosophy of fast-track surgery departments., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: Remimazolam is an ultrashort-acting benzodiazepine that is increasingly used for its efficacy in anesthesia induction and maintenance. However, limited research has explored its impact on intraoperative hypothermia compared to that of traditional inhalation anesthetics. This study aimed to compare the incidence of hypothermia during endoscopic nasal surgery when using remimazolam for maintenance anesthesia versus using inhalation anesthetics., Methods: This prospective study included 70 patients who underwent endoscopic nasal surgery under general anesthesia. The patients were randomly assigned to one of two groups: the inhalation anesthetic (IA) group (n=35), in which desflurane and nitrous oxide were administered, and the remimazolam (R) group (n=35), in which remimazolam and remifentanil were administered for anesthesia maintenance. The primary outcome was the incidence of intraoperative hypothermia, defined as an esophageal temperature below 36 °C during anesthesia., Results: The incidence of intraoperative hypothermia was significantly higher in the R group than in the IA group (P = 0.014). Furthermore, the temperature at the end of the surgery was significantly lower in the R group than in the IA group (P = 0.006). Additionally, the use of warming devices after surgery was more frequent in the R group than in the IA group (P = 0.047)., Conclusions: These findings suggest that the use of remimazolam for maintenance anesthesia during endoscopic nasal surgery increases the risk of intraoperative hypothermia compared to the use of inhalation anesthetics. This highlights the importance of temperature monitoring in patients receiving remimazolam to minimize the adverse outcomes associated with hypothermia during surgery., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Aims: This study is designed to identify risk factors of postoperative nausea and vomiting (PONV) in patients after gynecologic laparoscopic surgery and establish a nomogram model., Methods: In this retrospective and multicenter study, we collected and analyzed data from 1233 patients who underwent gynecologic laparoscopic surgery. The Lasso algorithm was used to optimize the selection of independent variables in the development group. Multivariate logistic regression analysis was used to explore the risk factors of PONV to develop the predictive nomogram model. Finally, we used an internal and external verification group and machine learning (ML) to evaluate the accuracy and clinical applicability of the model., Results: The dosage of sufentanil in patient-controlled intravenous analgesia (PCIA), the dosage of remifentanil, the use of neostigmine, duration of surgery and the maximum value of the P ET CO 2 were risk factors of PONV in patients after gynecologic laparoscopic surgery. In contrast, the dosage of propofol during the surgery and the use of steroids were protective factors. The nomogram was then established to predict the incidence of PONV in these patients based on the above eight indicators. The C-index of the development group, internal, and external verification groups are 0.802, 0.857, and 0.966, respectively., Conclusion: A nomogram model was developed to predict the incidence of PONV in patients after gynecologic laparoscopic surgery. This model was found to be reliable and of high clinical value., (© 2024. The Author(s).)

Background: The intraoperative autonomic neural blockade (ANB) was found safe and effective in controlling pain and associated symptoms and reducing analgesic consumption after laparoscopic sleeve gastrectomy (LSG). This study evaluated whether ANB performed at the outset of LSG reduces anesthetic consumption and promotes hemodynamic stability., Methods: This prospective, double-blinded, randomized trial involved patients undergoing LSG in 2 high-volume institutions. Patients were randomized to receive ANB either at the onset or the end of the procedure. The primary outcome measure was the consumption of remifentanil and sevoflurane. Secondary outcomes included Aldrete scale score differences in the recovery room and hemodynamic stability during the surgery., Results: In total, 80 patients (40 in the ANB at the onset group and 40 in the control group) were included for analysis. The consumption of remifentanil was significantly lower in the onset group compared to the control group (mean difference -0.04 mcg/kg/min, 95% confidence interval [CI], -0.06 to -0.02; P < .0001). There were no differences in the Aldrete scale scores between the 2 groups. Mean heart rate (HR) and mean arterial pressure (MAP) were also significantly less during surgery in the ANB at the onset group. No complications related to the ANB occurred., Conclusions: Performing ANB at the onset of LSG is a safe and effective approach that reduces remifentanil consumption and promotes hemodynamic stability during the procedure. This technique holds promise for optimizing anesthesia management in LSG and other minimally invasive surgeries., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society.)

Background: Remifentanil, an ultra-short-acting µ-opioid receptor agonist, is commonly used for anesthetic management due to excellent adjustability. Remifentanil is known to cause sinus bradycardia, however, because it has a direct negative chronotropic effect on the cardiac conduction system and there is an indirect negative chronotropic effect via the parasympathetic nervous system., Case Presentation: An 8-year-old Japanese boy was diagnosed with acute hydrocephalus due to a brain tumor in the fourth ventricle and underwent emergency surgery. Imaging examination showed brainstem compression. Endoscopic third ventriculostomy and ventriculoperitoneal shunt surgery were scheduled. Remifentanil was started during induction of general anesthesia, but electrocardiogram showed sinus bradycardia, then Wenckebach-type atrioventricular block, and then complete atrioventricular block. Remifentanil was immediately discontinued, and we administered atropine sulfate. Complete atrioventricular block was restored to sinus rhythm. When remifentanil was restarted, however, the electrocardiogram again showed sinus bradycardia, Wenckebach-type atrioventricular block, and then complete atrioventricular block. Remifentanil was again immediately discontinued, we administered adrenaline, and then complete atrioventricular block was restored to sinus rhythm. Fentanyl was used instead of remifentanil with continuous infusion of dopamine. There has since been no further occurrence of complete atrioventricular block., Conclusions: This is the first known case of complete atrioventricular block in a pediatric patient with increased intracranial pressure seemingly caused by administration of remifentanil., (© 2024. The Author(s).)

Remifentanil-induced hyperalgesia (RIH) is a part of a general opioid-induced hyperalgesia (OIH) syndrome, seemingly resulting from abrupt cessation of continuous remifentanil infusion at rates equal or exceeding 0.3 mcg/kg/min. The intricate mechanisms of its development are still not completely understood. However, hyperactivation of the N -methyl d -aspartate receptor system, descending spinal facilitation and increased concentration of dynorphin (a κ-opioid ligand) are commonly proposed as possible mechanisms. Several ways of prevention and management have been suggested, such as slow withdrawal of remifentanil infusion, the addition of propofol, pretreatment with or concomitant administration of ketamine, buprenorphine, cyclooxygenase-2 inhibitors (NSAIDs), methadone, dexmedetomidine. In clinical and animal studies, these strategies exhibited varying success, and many are still being investigated., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The occurrence of hypotension after induction of general anaesthesia is common in geriatric patients, and should be prevented to minimise perioperative complications. Compared with propofol, remimazolam potentially has a lower incidence of hypotension. This study aimed to compare the incidence of hypotension after general anaesthesia induction with remimazolam or propofol in geriatric patients., Methods: This single-centre, double-blind, randomised trial enrolled 90 patients aged ≥80 yr who received general anaesthesia for scheduled surgery. Patients were randomised to receive remimazolam (12 mg kg -1 h -1 ) or propofol (0.025 mg kg -1 s -1 ) for anaesthesia induction, with remifentanil and sevoflurane. The presence or absence of hypertension on the ward served as the stratification factor. The incidence of hypotension after the induction of general anaesthesia, defined as a noninvasive mean arterial pressure of <65 mm Hg measured every minute from initiation of drug administration to 3 min after tracheal intubation, was the primary outcome. Subgroup analysis was performed for the primary outcome using preoperative ward hypertension, clinical frailty scale, Charlson Comorbidity Index, and age., Results: Three subjects were excluded before drug administration, and 87 subjects were included in the analysis. The incidence of hypotension was 72.1% (31/43) and 72.7% (32/44) with remimazolam or propofol, respectively. No statistically significant differences (adjusted odds ratio, 0.96; 95% confidence interval, 0.37-2.46; P=0.93) were observed between groups. Subgroup analysis revealed no significant differences between groups., Conclusions: Compared with propofol, remimazolam did not reduce the incidence of hypotension after general anaesthesia induction in patients aged ≥80 yr., Clinical Trial Registration: UMIN000042587., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Serotonin syndrome (SS) is a life-threatening condition caused by serotonergic medications. We describe a unique case of SS likely caused by prolonged exposure to propofol and remifentanil alone. A young male presented for vestibular schwannoma resection. Several hours into the case, the patient demonstrated hyperthermia and hemodynamic instability, followed by clonus, rigidity, shivering, and tachycardia after emergence. SS was diagnosed using Hunter's criteria and improved with supportive measures. While the patient endorsed a history of methamphetamine use, his urine drug screen was negative. The possibility of SS should be considered when administering propofol and remifentanil, particularly with prolonged infusions., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Anesthesia Research Society.)

Objective: This study aimed to evaluate the incidence of early (up to 2 h) and late (2-24 h) postoperative nausea and vomiting (PONV) and hypotension in patients who underwent general anesthesia for orthognathic surgery using propofol or remimazolam along with remifentanil., Methods: This retrospective chart review included healthy adult patients under the age of 60 who underwent orthognathic surgery using propofol (P group) or remimazolam (R group) from January 2021 to March 2022. Records were reviewed to gather PONV and intraoperative hypotension data as well as patient characteristics and other variables., Results: Early PONV was significantly lower in the P group vs the R group (9.5% vs 34.1%, respectively; P = .002), although the difference in late PONV was insignificant (36.9% vs 51.2%, respectively; P = .13). A higher incidence of intraoperative hypotension was noted in the P group (22.6%) vs the R group (2.4%; P = .004); however, there were no differences in average intraoperative systolic blood pressure or vasopressor administration., Conclusion: These results suggest that propofol is associated with a lower incidence of early PONV as compared to remimazolam; however, antiemetics are still recommended given the frequency of late PONV in both groups. Propofol also caused more episodes of intraoperative hypotension vs remimazolam, but the increase in transient hypotension is likely to be irrelevant during orthognathic surgery in healthy adults under the age of 60.

Remifentanil‑induced hyperalgesia (RIH) is characterized by the emergence of stimulation‑induced pain, including phenomena such as allodynia and thermal hyperalgesia following remifentanil infusion. As a sequence‑specific DNA binding transcription factor, PAX6 positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system. It was hypothesized that puerarin could relieve RIH via targeting PAX6 to regulate transcription of transient receptor potential cation channel subfamily V Member 1 (TRPV1). A total of 32 rats were randomly divided into five groups, namely control group, RI group, RI + 10 mg/kg puerarin group (RI + puerarin10), RI + 20 mg/kg puerarin group (RI + puerarin20), and RI + 40 mg/kg puerarin group (RI + puerarin40). Mechanical and thermal hyperalgesia were tested at ‑24, 2, 6, 24 and 48 h after remifentanil infusion. Following the sacrifice of rats after the last behavioral test, western blot was used to detect the expression levels of TRPV1 in the tissues; Immunofluorescence staining and western blotting were used to detect the expression of PAX6 in the spinal cord. PharmMapper and JASPAR were used to predict the binding sites of puerarin/PAX6/TRPV1. Chromatin immunoprecipitation‑PCR and dual luciferase reporter assay were used to verify the targeting relationship between PAX6 and TRPV1. Immunofluorescence was used to detect the expression levels of TRPV1 and p‑NR2B. The results revealed that puerarin (10, 20, 40 mg/kg) dose‑dependently reduced thermal and mechanical hyperalgesia from 2 to 48 h after remifentanil infusion. Remifentanil infusion remarkably stimulated the expression of phosphorylated (p‑)NR2B. Nevertheless, the increased amount of p‑NR2B by RIH was dose‑dependently suppressed by puerarin in rats. In conclusion, puerarin was revealed to attenuate postoperative RIH via targeting PAX6 to regulate the transcription of TRPV1.

Objectives: Our purpose was to explore the effect of remifentanil on acute and chronic postsurgical pain after cardiac surgery., Materials and Methods: Randomized controlled trials were retrieved from electronic databases, such as PubMed, Cochrane Library, China National Knowledge Internet databases, Scopus, and Web of Science. A systematic review, meta-analysis, and trial sequential analysis (TSA) were performed. Basic information and outcomes were extracted from the included studies. The primary outcome was chronic postsurgical pain. Secondary outcomes were scores of postsurgical pain and morphine consumption within 24 hours after cardiac surgery. Risk of bias (ROB) assessment was based on the Cochrane ROB tool version 2. The overall quality of the evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system., Results: Seven studies consisting of 658 patients were enrolled in the meta-analysis. A single study had a high ROB and 2 studies had a moderate ROB. The incidence of chronic postsurgical pain (4 studies [415 patients]; risk ratio: 1.02 [95% CI: 0.53 to 1.95]; P = 0.95; I2 = 59%; TSA-adjusted CI: 0.78 to 1.20) and the postsurgical pain score (2 studies [196 patients]; mean difference: 0.09 [95% CI: -0.36 to 0.55]; P = 0.69; I2 = 0%; TSA-adjusted CI: -0.36 to 0.55) were not statistically different between the 2 groups. However, morphine consumption (6 studies [569 patients]; mean difference: 6.94 [95% CI: 3.65 to 10.22]; P < 0.01; I2 = 0%; TSA-adjusted CI: 0.00 to 0.49) was higher in the remifentanil group than in the control group., Conclusion: There was not enough evidence to prove that remifentanil can increase the incidence of chronic postsurgical pain after cardiac surgery, but interestingly, the results tended to support a trend toward increased complications in the intervention group. However, there was moderate certainty evidence that the use of remifentanil increases the consumption of morphine for analgesia, and more direct comparison trials are needed to inform clinical decision-making with greater confidence., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives : The analgesia/nociception index (ANI) potentially monitors nociceptive status during anesthesia, but its link to preoperative pain sensitivity is unclear. We investigated the relationship between pre-anesthetic ANI scores and propofol injection pain (PIP) in patients receiving remifentanil. Materials and Methods : This study included 124 male patients aged 19-60 undergoing general anesthesia (ASA class I or II). Patients were randomized to group R ( n = 62, remifentanil 4 ng/mL) or group C ( n = 62, saline). The primary outcome was the association between PIP and ANI. Secondary outcomes included the incidence and severity of PIP or rocuronium-induced withdrawal movement (RIWM) and their association with ANI. Results : PIP and RIWM incidence and severity were lower in group R than in group C. A weak negative correlation between PIP and ANI at pre-induction (r pb = -0.21, p = 0.02, r pb = -0.37, p < 0.01) and a moderate negative correlation during propofol injection ( r pb = -0.48, p = 0.02) were observed. A significant negative correlation was found between RIWM and ANI during rocuronium injection (τb = -0.61, p < 0.01). AUC, cut-off value, specificity, and sensitivity in ANI at pre-induction for predicting PIP were 0.67 ( p = 0.02), 59, 76%, and 55%, respectively. AUC, cut-off value, specificity, and sensitivity in ANI during propofol injection for PIP were 0.77 ( p < 0.01), 65, 81%, and 67%, respectively. Conclusions : ANI scores demonstrated significant differences between groups, suggesting potential predictive value for PIP despite the low pre-induction AUC value. This study highlights the potential of using ANI scores to predict and manage PIP in patients receiving remifentanil.

Background: This meta-analysis aimed to explore the correlation between the different doses of remifentanil-based anaesthesia and postoperative pain in randomised trials., Methods: The electronic databases including PubMed, Cochrane, clinical trial registries, and Google Scholar were searched up to November 2022 for randomised controlled trials (RCTs) that assessed the dose dependent efficacy of remifentanil for postoperative pain intensity and hyperalgesia., Results: 31 studies involving 2019 patients were included for analysis. Compared with the high remifentanil dose administration, patients in low doses showed less postoperative pain intensity at 1-2 h (weighted mean differences (WMD): 0.60, 95% CI, 0.05 to 1.15), 3-8 h (WMD: 0.38, 95% CI, 0.00 to 0.75), 24 h (WMD: 0.26, 95% CI, 0.04 to 0.48) and 48 h (WMD: 0.32, 95% CI, 0.09 to 0.55). Remifentanil-free regimen failed to decrease the pain score at 24 h (WMD: 0.10, 95% CI, -0.10 to 0.30) and 48 h (WMD: 0.15, 95% CI, -0.22 to 0.52) in comparison with remifentanil-based anaesthesia. After excluding trials with high heterogeneity, the dose of the remifentanil regimen was closely correlated with the postoperative pain score (P=0.03). In addition, the dose of the remifentanil regimen was not associated with the incidence of postoperative nausea and vomiting (PONV) (P=0.37)., Conclusions: Our meta-analysis reveals that the low dose of remifentanil infusion is recommendable for general anaesthesia maintenance. No evidence suggests that remifentanil-free regimen has superiority in reducing postoperative pain. Moreover, remifentanil doesn't have a dose dependent effect in initiating PONV., Trial Registration: The protocol of present study was registered with PROSPERO (CRD42022378360)., (© 2024. The Author(s).)

Background: Opioids are metabolised by enzymes the activities of which vary with the circadian rhythm. We examined whether opioid infusions administered at different times of the day produce varying degrees of opioid-induced hyperalgesia (OIH) in animal experiments and clinical studies., Methods: Male Sprague-Dawley rats received remifentanil infusions (1 μg kg -1 ·min -1 for 1 h) at Zeitgeber times (ZT) 0, 4, 8, 12, 16, or 20 h. Rhythmicity of mechanical hypersensitivity was assayed after the infusion. Mechanical hypersensitivity, drug concentration, and metabolic enzyme activity of Wistar rats that received sufentanil (10 μg kg -1 ; four consecutive i.p. injections at 15-min intervals) or remifentanil infusion at ZT0 or ZT8 were assayed. Sixty patients who underwent abdominal laparoscopic surgery under general anaesthesia received remifentanil infusion (0.15 μg kg -1 min -1 ) and sufentanil injection (0.2 μg kg -1 ) at induction and skin incision, respectively. Postoperative pressure pain sensitivity, pain Numeric Rating Scale (NRS), drug concentrations, and nonspecific esterase activity were assessed., Results: Sprague-Dawley rats that received remifentanil infusion exhibited a robust rhythmic paw withdrawal threshold (JTK&#95;CYCLE: P=0.001, Q=0.001, Phase=26). Wistar rats infused with remifentanil or sufentanil at ZT8 exhibited greater OIH (P<0.001) than those infused at ZT0, with higher blood concentrations (P<0.001) and lower metabolic enzyme activities (P=0.026 and P=0.028, respectively). Patients in the afternoon group exhibited higher pressure pain sensitivity at forearm (P=0.002), higher NRS (P<0.05), higher drug concentrations (sufentanil: P=0.037, remifentanil: P=0.005), and lower nonspecific esterase activity (P=0.024) than the morning group., Conclusions: Opioid infusions administered at different times of day produced varying degrees of OIH, possibly related to circadian rhythms of metabolic enzyme activities., Clinical Trial Registration: NCT05234697., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Remifentanil (Remi)-induced hyperalgesia is a serious but common postoperative clinical problem. Sirtuin 2 (SIRT2) is essential in the pathogenetic mechanisms of several neurological disorders. However, whether SIRT2 contributes to the modulation of Remi-induced postsurgical hyperalgesia (POH) is unknown. Here, we investigated the regulatory potential of SIRT2 in Remi-stimulated POH. A rat Remi-stimulated POH model was built by infusing Remi in the surgical incision. Mechanical allodynia and thermal hyperalgesia were separately assessed by paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) measurements. SIRT2 and binding adaptor molecule 1 (Iba1) protein expressions and localization in spinal cord samples were detected by western blot and immunofluorescence. The results revealed SIRT2 downregulation in the spinal cord of rats with Remi-stimulated POH. Intrathecal administration of the overexpression plasmid harboring SIRT2 remarkably relieved mechanical allodynia, along with thermal hyperalgesia in the model animals. Iba1 amounts were increased upon intraoperative incision or Remi infusion, and this effect was more pronounced upon combining both treatments. Furthermore, SIRT2 overexpression suppressed microglia activation in the spinal cord of model animals, and starkly relieved incision- and/or Remi-associated pronociceptive processes as well as spinal microglia activation. SIRT2 elevation relieved Remi-associated POH, likely by suppressing spinal microglia activation. Thus, SIRT2 could be a potent target for treating neuropathic pain.

Purpose of Review: There are various pharmacokinetic-dynamic models available, which describe the time course of drug concentration and effect and which can be incorporated into target-controlled infusion (TCI) systems. For anesthesia and sedation, most of these models are derived from narrow patient populations, which restricts applicability for the overall population, including (small) children, elderly, and obese patients. This forces clinicians to select specific models for specific populations., Recent Findings: Recently, general purpose models have been developed for propofol and remifentanil using data from multiple studies and broad, diverse patient groups. General-purpose models might reduce the risks associated with extrapolation, incorrect usage, and unfamiliarity with a specific TCI-model, as they offer less restrictive boundaries (i.e., the patient "doesn't fit in the selected model") compared with the earlier, simpler models. Extrapolation of a model can lead to delayed recovery or inadequate anesthesia. If multiple models for the same drug are implemented in the pump, it is possible to select the wrong model for that specific case; this can be overcome with one general purpose model implemented in the pump., Summary: This article examines the usability of these general-purpose models in relation to the more traditional models., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Study Objective: To estimate the incidence of unwanted spontaneous responsiveness and burst suppression (BSupp) in patients undergoing state entropy (SE) and surgical pleth index (SPI)-guided total intravenous anesthesia (TIVA) with target-controlled infusion (TCI)., Design: Observational, prospective, single-center study., Settings: Operating room., Patients: 107 adult (<65 years) and elderly (≥65 years) women undergoing breast surgery., Interventions: Propofol-remifentanil TIVA-TCI-guided by SE for depth of anesthesia monitoring (target value 40-60) and SPI for antinociception monitoring (target value 20-50) without neuromuscular blockade., Measurements: Age; body mass index; American Society of Anesthesiologists physical status classification; concentration at the effect site of propofol (CeP) and remifentanil (CeR) at loss of responsiveness (LoR), median during anesthesia maintenance (MdM), and at return of responsiveness (RoR); propofol infusion duration; incidence of postoperative delirium (POD) with Confusing Assessment Method for the Intensive Care Unit., Main Results: During SE-SPI-guided TIVA-TCI, 13.1% of patients showed unwanted spontaneous responsiveness, whereas 45.8% showed BSupp. Unwanted spontaneous responsiveness was observed mainly in adults (p < 0.05), and higher CeP RoR (p < 0.05) was registered. BSupp was observed mainly in patients showing a lower CeP MdM (p < 0.01) and CeP RoR (p < 0.05). Unwanted spontaneous responsiveness and BSupp were not associated with significant differences in CeRs. An age-related hysteresis effect was observed, resulting in higher CeP LoR than CeP RoR (p < 0.001). 12.2% of patients showed POD. Only preoperative serum albumin was associated with increased likelihood of POD (p = 0.046)., Conclusions: The SE-SPI-guided TIVA-TCI did not prevent unwanted spontaneous responsiveness and BSupp. CeP RoR may be used as a proxy for anesthetic sensitivity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The liberal use of remifentanil in spine surgery has been associated with an increased incidence of postoperative hyperalgesia. Nevertheless, controversies remain as the existing evidence is inconclusive to determine the relationship between remifentanil use and the development of opioid-induced hyperalgesia. We hypothesized that intraoperative infusion of higher dose remifentanil during scoliosis surgery is associated with postoperative hyperalgesia, manifesting clinically as greater postoperative morphine consumption and pain scores., Methods: Ninety-seven patients with adolescent idiopathic scoliosis (AIS) who underwent posterior spinal fusion surgery at a single tertiary institution from March 2019 until June 2020 were enrolled in this retrospective study. Anesthesia was maintained using a target-controlled infusion of remifentanil combined with volatile anesthetic desflurane in 92 patients, while five patients received it as part of total intravenous anesthesia. Intravenous ketamine, paracetamol, and fentanyl were administered as multimodal analgesia. All patients received patient-controlled analgesia (PCA) morphine postoperatively. Pain scores at rest and on movement, assessed using the numerical rating scale, and the cumulative PCA morphine consumption were collected at a six-hourly interval for up to 48 h. According to the median intraoperative remifentanil dose usage of 0.215 µg/kg/min, patients were divided into two groups: low dose and high dose group., Results: There were no significant differences in the pain score and cumulative PCA morphine consumption between the low and high dose remifentanil group. The mean duration of remifentanil infusion was 134.9 ± 22.0 and 123.4 ± 23.7 min, respectively., Conclusion: Intraoperative use of remifentanil as an adjuvant in AIS patients undergoing posterior spinal fusion surgery was not associated with postoperative hyperalgesia., (© 2023. The Author(s).)

Importance: It is uncertain whether a rapid-onset opioid is noninferior to a rapid-onset neuromuscular blocker during rapid sequence intubation when used in conjunction with a hypnotic agent., Objective: To determine whether remifentanil is noninferior to rapid-onset neuromuscular blockers for rapid sequence intubation., Design, Setting, and Participants: Multicenter, randomized, open-label, noninferiority trial among 1150 adults at risk of aspiration (fasting for <6 hours, bowel occlusion, recent trauma, or severe gastroesophageal reflux) who underwent tracheal intubation in the operating room at 15 hospitals in France from October 2019 to April 2021. Follow-up was completed on May 15, 2021., Interventions: Patients were randomized to receive neuromuscular blockers (1 mg/kg of succinylcholine or rocuronium; n = 575) or remifentanil (3 to 4 μg/kg; n = 575) immediately after injection of a hypnotic., Main Outcomes and Measures: The primary outcome was assessed in all randomized patients (as-randomized population) and in all eligible patients who received assigned treatment (per-protocol population). The primary outcome was successful tracheal intubation on the first attempt without major complications, defined as lung aspiration of digestive content, oxygen desaturation, major hemodynamic instability, sustained arrhythmia, cardiac arrest, and severe anaphylactic reaction. The prespecified noninferiority margin was 7.0%., Results: Among 1150 randomized patients (mean age, 50.7 [SD, 17.4] years; 573 [50%] women), 1130 (98.3%) completed the trial. In the as-randomized population, tracheal intubation on the first attempt without major complications occurred in 374 of 575 patients (66.1%) in the remifentanil group and 408 of 575 (71.6%) in the neuromuscular blocker group (between-group difference adjusted for randomization strata and center, -6.1%; 95% CI, -11.6% to -0.5%; P = .37 for noninferiority), demonstrating inferiority. In the per-protocol population, 374 of 565 patients (66.2%) in the remifentanil group and 403 of 565 (71.3%) in the neuromuscular blocker group had successful intubation without major complications (adjusted difference, -5.7%; 2-sided 95% CI, -11.3% to -0.1%; P = .32 for noninferiority). An adverse event of hemodynamic instability was recorded in 19 of 575 patients (3.3%) with remifentanil and 3 of 575 (0.5%) with neuromuscular blockers (adjusted difference, 2.8%; 95% CI, 1.2%-4.4%)., Conclusions and Relevance: Among adults at risk of aspiration during rapid sequence intubation in the operating room, remifentanil, compared with neuromuscular blockers, did not meet the criterion for noninferiority with regard to successful intubation on first attempt without major complications. Although remifentanil was statistically inferior to neuromuscular blockers, the wide confidence interval around the effect estimate remains compatible with noninferiority and limits conclusions about the clinical relevance of the difference., Trial Registration: ClinicalTrials.gov Identifier: NCT03960801.

Opioid-induced hyperalgesia (OIH) is a state of paradoxically enhanced pain transmission, termed nociceptive sensitization, described to occur in both humans and animals after repeated administration of opioid drugs, including rapidly acting remifentanil. However, molecular mechanisms of OIH remain understudied. In this issue of the JCI, Yan Jin and colleagues provided strong evidence that hyperexcitable thalamocortical networks drive remifentanil-induced hyperalgesia in a rodent model of postsurgical pain. Furthermore, the authors specifically identified an important role of the CaV3.1 isoform of low-voltage-activated or T-type calcium channels (T-channels) in this process. Further experiments are needed to determine whether thalamic T channels could serve as targets for the treatment of OIH.

Remifentanil-induced hyperalgesia (RIH) is a severe but common postoperative clinical problem with elusive underlying neural mechanisms. Here, we discovered that glutamatergic neurons in the thalamic ventral posterolateral nucleus (VPLGlu) exhibited significantly elevated burst firing accompanied by upregulation of Cav3.1 T-type calcium channel expression and function in RIH model mice. In addition, we identified a glutamatergic neuronal thalamocortical circuit in the VPL projecting to hindlimb primary somatosensory cortex glutamatergic neurons (S1HLGlu) that mediated RIH. In vivo calcium imaging and multi-tetrode recordings revealed heightened S1HLGlu neuronal activity during RIH. Moreover, preoperative suppression of Cav3.1-dependent burst firing in VPLGlu neurons or chemogenetic inhibition of VPLGlu neuronal terminals in the S1HL abolished the increased S1HLGlu neuronal excitability while alleviating RIH. Our findings suggest that remifentanil induces postoperative hyperalgesia by upregulating T-type calcium channel-dependent burst firing in VPLGlu neurons to activate S1HLGlu neurons, thus revealing an ion channel-mediated neural circuit basis for RIH that can guide analgesic development.

Renal injury is a fatal complication in critically ill patients with sepsis. As an ultrashort-acting synthetic opioid derivative, remifentanil has been reported to mitigate renal injury and sepsis. Nevertheless, whether remifentanil also suppresses sepsis-triggered renal injury is uncertain. The aim of this study was to investigate the effect of remifentanil on endoplasmic reticulum stress (ERS) and inflammatory response in an in vitro lipopolysaccharide (LPS)-stimulated renal tubular epithelial cell (HK-2) model and its mechanism. The viability of HK-2 cells with the absence or presence of LPS treatment was surveyed by cell counting kit-8 assay. Under the condition of LPS treatment, apoptosis was appraised by TUNEL assay and western blot. Levels of inflammatory factors were estimated though corresponding kits. Western blot tested the expression of toll-like receptor 4 (TLR4)/nuclear factor-kappaB (NF-κB) signaling-associated proteins. Also, the expression of ERS-related proteins was detected by western blot. Further, ERS inducer tunicamycin (TM) was added and the aforementioned experiments were conducted again. The results underlined the protective effects of remifentanil on LPS-evoked viability injury, inflammation, activation of TLR4/NF-κB signaling and ERS in HK-2 cells. Moreover, the impacts of remifentanil on the biological events of LPS-insulted HK-2 cells were all reversed by TM administration. To conclude, remifentanil might have a remarkable ameliorative effect on sepsis-induced renal injury, which implied the potential of remifentanil-based drug therapy in sepsis-induced renal injury.

Study Objective: The quality of recovery (QoR) of remimazolam-based and propofol-based total intravenous anesthesia was compared as measured by QoR-15 scores., Design: A prospective, double-blind, randomized controlled, non-inferiority trial., Setting: An operating room, a post-anesthesia care unit (PACU), and a hospital ward., Patients: Female patients (n = 140; 20-65 years) scheduled for open thyroidectomy were enrolled and randomly assigned to the remimazolam or propofol group., Interventions: The remimazolam group received continuous remimazolam infusions and effect-site target-controlled remifentanil infusions. The propofol group received effect-site target-controlled infusions of propofol and remifentanil., Measurements: The primary outcome was QoR-15 on postoperative day 1 (POD1). The mean difference between the groups was compared against a non-inferiority margin of -8. Secondary outcomes were QoR-15 on POD2, hemodynamic data, time to lose and recover consciousness, sedation score upon PACU admission, pain, and postoperative nausea and vomiting profiles at the PACU and ward. Group-time interaction effects in hemodynamic data and QoR-15 were analyzed using a linear mixed model., Main Results: The total QoR-15 score on POD1 in the remimazolam group was non-inferior to that in the propofol group (mean [SD] 111.2 [18.8] vs. 109.1 [18.9]; mean difference [95% CI] 2.1 [-4.2, 8.5]; p = 0.002 for non-inferiority). The QoR-15 score on POD2 was comparable between the groups, and no group-time interaction was observed. At the end of anesthesia, after extubation, and upon arrival at the PACU, mean arterial pressure was significantly higher in the remimazolam group. Remimazolam group was more sedated at the time of admission to PACU. Pain intensity and the requirement for analgesics were lower in the remimazolam group than in the propofol group., Conclusions: Remimazolam-based total intravenous anesthesia provided a similar QoR to propofol. Remimazolam and propofol can be used interchangeably for general anesthesia in female patients undergoing thyroid surgery., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: We compared dexmedetomidine-remifentanil vs. propofol-remifentanil in terms of safety and quality during sedation for Endobronchial ultrasonography (EBUS)., Methods: A randomized, double-blind trial. Outpatients undergoing EBUS randomly received 1 μg/kg/hour dexmedetomidine or a target concentration of 2.5 μg/mL propofol, both combined with remifentanil initially targeted at 1.5 ng/mL and subsequently titrated. Additional sedatives were restricted. The primary outcome was the need for airway rescue interventions to treat oxygen desaturation., Results: Twenty-eight patients received dexmedetomidine-remifentanil and 27 received propofol-remifentanil. Airway rescue interventions were fewer in the dexmedetomidine group vs. the propofol one (23 vs. 76% patients, relative risk 3.21 (95% CI 1.55-6.64, P < 0.002)). Desaturation in the dexmedetomidine group was always resolved by increasing nasal oxygen flow, whereas additional interventions were needed in 60% of patients receiving propofol. Hypotension was more frequent in the propofol group, while hypertension, bradycardia and coughing were similar in both. Bronchoscopists' and patients' satisfaction were similar, although in the dexmedetomidine group two patients needed additional sedatives and two patients would not repeat the sedation technique., Conclusion: Moderate sedation with dexmedetomidine-remifentanil for EBUS is safer than deep sedation with propofol-remifentanil but it would occasionally need additional sedatives to ensure patient satisfaction.

Background: Animal data suggest that the antidepressant and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator tianeptine is able to prevent opioid-induced respiratory depression. The hypothesis was that oral or intravenous tianeptine can effectively prevent or counteract opioid-induced respiratory depression in humans., Methods: Healthy male and female volunteers participated in two studies that had a randomized, double blind, placebo-controlled, crossover design. First, oral tianeptine (37.5-, 50-, and 100-mg doses with 8 subjects) pretreatment followed by induction of alfentanil-induced respiratory depression (alfentanil target concentration, 100 ng/ml) was tested. Primary endpoint was ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg (V̇E55). Next, the ability of four subsequent and increasing infusions of intravenous tianeptine (target tianeptine plasma concentrations 400, 1,000, 1,500, and 2,000 ng/ml, each given over 15 min) to counteract remifentanil-induced respiratory depression was determined in 15 volunteers. Ventilation was measured at isohypercpania (baseline ventilation 20 ± 2 l/min). The primary endpoint was minute ventilation during the 60 min of tianeptine versus placebo infusion., Results: Alfentanil reduced V̇E55 to 13.7 (95% CI, 8.6 to 18.8) l/min after placebo pretreatment and to 17.9 (10.2 to 25.7) l/min after 50-mg tianeptine pretreatment (mean difference between treatments 4.2 (-11.5 to 3.0) l/min, P = 0.070). Intravenous tianeptine in the measured concentration range of 500 to 2,000 ng/ml did not stimulate ventilation but instead worsened remifentanil-induced respiratory depression: tianeptine, 9.6 ± 0.8 l/min versus placebo 15.0 ± 0.9 l/min; mean difference, 5.3 l/min; 95% CI, 2.5 to 8.2 l/min; P = 0.001, after 1 h of treatment., Conclusions: Neither oral nor intravenous tianeptine were respiratory stimulants. Intravenous tianeptine over the concentration range of 500 to 2000 ng/ml worsened respiratory depression induced by remifentanil., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Dexmedetomidine is an α 2 agonist and remifentanil is a short-acting μ opioid agonist. We aimed to compare the dexmedetomidine and remifentanil infusions used for conscious sedation in geriatric patients undergoing outpatient cataract surgery in terms of sedation quality, side effects, and surgeon satisfaction. Eighty patients were allocated into two groups as per the administration of dexmedetomidine (dexmedetomidine group) and remifentanil (remifentanil group) infusion in this randomized, prospective, double-blinded study. In dexmedetomidine group (n = 40), after a loading of 1 μg/kg dexmedetomidine in 10 minutes, 0.4 μg/kg/h infusion was administered. In the remifentanil group (n = 40), remifentanil at a dose of 0.05 μg/kg was administered for 10 minutes, and then 0.05 μg/kg/min infusion was continued. Observer Assessment Warning/Sedation Scale values evaluating sedation quality were lower in the dexmedetomidine group than in the remifentanil group, although it was not statistically significant (P > 0.05). Bispectral Index values evaluating sedation quality were lower in the dexmedetomidine group according to the remifentanil group (P < 0.05). The dexmedetomidine group had lower Verbal Rating Scale and Visual Analogue Scale scores evaluating pain intensity compared with the remifentanil group (P < 0.05). The nausea Visual Analogue Scale values evaluating the severity of postoperative nausea in the dexmedetomidine group were lower than those in the remifentanil group (P < 0.05). The surgeon satisfaction was found to be greater in the dexmedetomidine group compared with the remifentanil group (P = 0.015). In geriatric patients, the targeted sedation and analgesia levels were achieved more easily with dexmedetomidine infusion, without hemodynamic and respiratory side effects, compared to remifentanil infusion., Competing Interests: None

Abstract: Opioids in general and remifentanil in particular can induce hyperalgesia. Preclinical data suggest that cannabidiol might have the capacity to reduce opioid-induced hyperalgesia (OIH). Thus, we investigated the effect of oral cannabidiol on OIH in healthy volunteers using an established pain model. Twenty-four healthy participants were included in this randomized, double-blinded, crossover study and received either a 1600-mg single-dose oral cannabidiol or placebo. Hyperalgesia, allodynia, and pain were induced by intracutaneous electrical stimulation. To provoke OIH, participants recieved an infusion of 0.1 µg/kg/min remifentanil over a time frame of 30 minutes, starting 100 minutes after oral cannabidiol ingestion. The primary outcome was the area of hyperalgesia (in square centimetres) up to 60 minutes after remifentanil administration. The area of allodynia (in square centimetres) and pain (numeric rating scale) were also assessed.Cannabidiol had no significant effect on hyperalgesia, allodynia, or pain at any time point of measurement compared with placebo. The area of hyperalgesia after remifentanil administration significantly increased compared with baseline (17.0 cm 2 [8.1-28.7] vs 25.3 cm 2 [15.1-39.6]; P = 0.013). Mean cannabidiol blood levels were 4.1 ± 3.0 µg/L (mean ± SD) at 130 minutes after ingestion and were 8.2 μg/L ± 6.9 µg/L (mean ± SD) at 200 minutes. Cannabidiol was well tolerated. We conclude that a high single-oral dose of 1600-mg cannabidiol is not effective in reducing OIH. Before excluding an effect of cannabidiol on OIH, research should focus on drug formulations enabling higher cannabidiol concentrations., (Copyright © 2022 International Association for the Study of Pain.)

In order to investigate the effect of remifentanil combined with propofol on awakening of craniotomy for tumor, a retrospective analysis is conducted. 86 patients who underwent craniotomy for brain tumor in our hospital from July 2020 to December 2021 are chosen to observe the quality of awakening, hemodynamic parameters, and the occurrence of adverse reactions. All patients are divided into group A ( n = 43) and group B ( n = 43) according to the use of anesthesia drugs. The intraoperative awakening quality and the hemodynamic parameters during different periods of the two groups are compared. The experimental results show that the incidence of postoperative adverse reactions in group B is significantly lower than that in group A ( P < 0.05). It is clearly evident that remifentanil combined with protocol has good intraoperative wake-up effect in craniotomy for tumor and maintain the hemodynamic stability of patients. Also, it can obtain high wake-up quality and effectively reduce postoperative adverse reactions., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Qiang Zhou et al.)

Background: The study was aimed to compare the efficacy and safety of different sedation protocols of dexmedetomidine-remifentanil and propofol-remifentanil for percutaneous closure of atrial septal defects (ASD) under transthoracic echocardiography (TTE) guidance., Material and Methods: From March 2020 to January 2021, of 114 patients screened, 59 ASD patients scheduled for percutaneous closure under TTE guidance were randomly allocated into the dexmedetomidine-remifentanil (D-R) group (n = 29) and the propofol-remifentanil (P-R) group (n = 30). The incidence of hemodynamic and respiratory adverse events, arterial blood gas analysis, induction and recovery time, pain score, infusion rate of remifentanil, satisfaction of the surgeon and patient, additional sedatives were collected for analysis and comparison., Results: The induction time was longer in the D-R group than that in the P-R group (17.66 ± 2.65 min vs 11.43 ± 1.48 min; difference, 6.22 min; 95% CI 5.10 to 7.35; P < 0.001). No differences were observed in the 2 groups in terms of the additional sedatives, infusion rate of remifentanil, pain score, recovery time (P > 0.05). There was no difference between the two groups regarding the incidence of cardiovascular adverse events (6 [20.7%] vs 4 [13.3%]; difference, 7.4%; 95% CI - 11.7 to 26.5%; P = 0.506). Respiratory adverse events occurred in 1 patient (3.4%) in the D-R group, and 8 patients (26.7%) in the P-R group (difference, 23.3%; 95% CI 6.2 to 40.5%; P = 0.026). The incidence of hypercapnia was significantly lower in the D-R group (4 [13.8%]) than in the P-R group (13 [43.3%]; difference, 29.5%; 95% CI 7.8 to 51.2%; P = 0.012)., Conclusions: Except for more rapid the induction time and higher the surgeon satisfaction score in the propofol-remifentanil protocol, the efficacy was similar between two sedation protocols. The hemodynamic stability was comparable, the dexmedetomidine-remifentanil protocol had superior airway security due to fewer hypercapnia and respiratory adverse events., (© 2022. The Author(s).)

Background: Opioid-induced respiratory depression can be partially antagonized in the preBötzinger Complex and Parabrachial Nucleus/Kölliker-Fuse Complex. We hypothesized that additional opioid antagonism in the caudal medullary raphe completely reverses the opioid effect., Methods: In adult ventilated, vagotomized, decerebrate rabbits, we administrated remifentanil intravenously at "analgesic", "apneic", and "very high" doses and determined the reversal with sequential naloxone microinjections into the bilateral Parabrachial Nucleus/Kölliker-Fuse Complex, preBötzinger Complex, and caudal medullary raphe. In separate animals, we injected opioid antagonists into the raphe without intravenous remifentanil., Results: Sequential naloxone microinjections completely reversed respiratory rate depression from "analgesic" and "apneic" remifentanil, but not "very high" remifentanil concentrations. Antagonist injection into the caudal medullary raphe without remifentanil independently increased respiratory rate., Conclusions: Opioid-induced respiratory depression results from a combined effect on the respiratory rhythm generator and respiratory drive. The effect in the caudal medullary raphe is complex as we also observed local antagonism of endogenous opioid receptor activation, which has not been described before., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Severe postoperative pain remains a major problem that is seen in 20 to 40% of patients. The Analgesia/Nociception Index (ANI) is a 0-100 index reflecting the relative parasympathetic activity allowing for intraoperative analgesia monitoring. We have previously shown that an ANI value < 50 immediately before extubation may predict the occurrence of immediate postoperative pain with good performance. We hypothesized that GOAL-Directed ANalgesia may provide reduced immediate postoperative pain and optimized intraoperative remifentanil administration (GOLDAN study)., Methods: The GOALDAN study is an international, multicenter, simple-blind, parallel, prospective, randomized, controlled, two-armed trial. Patients are randomly assigned in a 1:1 ratio in the control group or in the experimental group. Patients will be randomly allocated to either the intervention group (ANI) or the control group (standard care only). In the ANI group, the administration of remifentanil will be goal-directed targeting a 50-80 ANI range, with a prophylactic injection of morphine immediately after extubation if the case of ANI < 50. Our primary objective was to determine whether the prophylactic administration of morphine at the end of the procedure in patients at risk of immediate postoperative pain (ANI < 50 immediately before extubation) could reduce the incidence of the latter by 50% in the post-anesthetic care unit. Our secondary objective was to determine whether the intraoperative use of goal-directed analgesia with an ANI target of 50 to 80 could improve intraoperative hemodynamics and postoperative outcome., Discussion: Because of the paucity of well-conducted trials, the authors believe that a randomized-controlled trial will improve the evidence for using analgesia monitoring during general anesthesia and strengthen current recommendations for intraoperative analgesia management., Trial Registration: ClinicalTrials.gov NCT03618082. Registered on 7 August 2018., (© 2022. The Author(s).)

Remifentanil is an ultra-short-acting opioid that sometimes causes opioid-induced hyperalgesia, which has led to controversy regarding the association between intraoperative remifentanil administration and postoperative pain. This study aimed to assess the effects of the intraoperative remifentanil dose on postoperative pain. Patients undergoing esophageal, gastric/hepatobiliary, or intestinal/colon surgery and using postoperative patient-controlled epidural analgesia were analyzed. The patients were divided into two groups based on the average intraoperative remifentanil dose (high-dose remifentanil [HR] group: ≥0.1 μg/kg/min; low-dose remifentanil [LR] group: <0.1 μg/kg/min). In all, 406 patients met the inclusion criteria. A significant difference in the average dose of remifentanil was seen between the groups during the anesthesia period (0.14±0.05 vs. 0.07±0.02 μg/kg/min). However, no significant difference was seen in pre- or intraoperative patient characteristics. Numerical rating scale (NRS) scores on postoperative day 1 were similar between the groups (HR: 1.7±2.0; LR: 1.7±2.0; p=0.74). The incidence of poor pain control (NRS > 3/10) was also similar between the groups (HR: 14%; LR: 16%; p=0.57). Older age (> 60 years) and type of surgery (esophageal surgery) were associated with worse postoperative NRS scores. No significant association was seen between the intraoperative remifentanil dose and postoperative NRS scores following thoracoabdominal surgery with postoperative epidural pain management., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background: Trafficking and activation of N-methyl-D-aspartate (NMDA) receptors play an important role in initiating and maintaining postoperative remifentanil-induced hyperalgesia (RIH). Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome has been linked to the development of inflammatory and neuropathic pain. We hypothesized that activation of NLRP3 inflammasome mediates IL-1β release and contributes to RIH in rats by increasing NMDA receptor NR1 (NR1) subunit phosphorylation and decreasing glutamate transporter-1 (GLT-1) expression., Methods: Acute exposure to remifentanil (1.2 μg/kg/min for 60 min) was used to establish RIH in rats. Thermal and mechanical hyperalgesia were tested at baseline (24 h before remifentanil infusion) and 2, 6, 24, and 48 h after remifentanil infusion. The levels of IL-1β, GLT-1, phosphorylated NR1 (phospho-NR1), and NLRP3 inflammasome activation indicators [NLRP3, Toll-like receptor 4 (TLR4), P2X purinoceptor 7 (P2X7R), and caspase-1] were measured after the last behavioral test. A selective IL-1β inhibitor (IL-1β inhibitor antagonist; IL-1ra) or three different selective NLRP3 inflammasome activation inhibitors [(+)-naloxone (a TLR4 inhibitor), A438079 (a P2X7R inhibitor), or ac-YVADcmk (a caspase-1 inhibitor)] were intrathecally administered immediately before remifentanil infusion into rats., Results: Remifentanil induced significant postoperative hyperalgesia, increased IL-1β and phospho-NR1 levels and activated the NLRP3 inflammasome by increasing TLR4, P2X7R, NLRP3, and caspase-1 expression, but it decreased GLT-1 expression in the L4-L6 spinal cord segments of rats, which was markedly improved by intrathecal administration of IL-1ra, (+)-naloxone, A438079, or ac-YVADcmk., Conclusion: NLRP3 inflammasome activation mediates IL-1β release and contributes to RIH in rats by inducing NMDA receptor NR1 subunit phosphorylation and decreasing GLT-1 expression. Inhibiting the activation of the NLRP3 inflammasome may be an effective treatment for RIH.

The experimental investigations on the pathogenesis of remifentanil-induced hyperalgesia (RIH) have been primarily conducted, but the effective treatment of RIH remains unclear. Recent reports highlight the necessity of ionotropic glutamate receptors in oxidative damage in spinal nociceptive transduction. Artesunate, the 1st-line anti-malaria drug, has been identified to be valid in removing superoxide in several pathological conditions. This study evaluated whether artesunate inhibits RIH via regulating metabotropic glutamate receptor 5 (mGluR5) and mitochondrial antioxidant enzyme peroxiredoxin-3 in rats. Artesunate was injected intrathecally 10 min before intravenous infusion of remifentanil (1 μg·kg -1 ·min -1 for 60 min) in rats. The antinociception of artesunate was verified by assessment of paw withdrawal mechanical threshold and paw withdrawal thermal latency. Spinal mGluR5 expression and peroxiredoxin-3 hyperacetylation were examined. Also, both the mGluR5 agonist DHPG and antagonist MPEP were utilized to explore the involvement of mGluR5 in the anti-hyperalgesic property of artesunate. Here, we found that artesunate (10 μg and 100 μg but not 1 μg) prevented RIH in a dose-dependent manner. Artesunate reduced remifentanil-related spinal over-expression of mGluR5 gene and protein, and hyperacetylation of peroxiredoxin-3. Intrathecal application of MPEP (10 nmol and 100 nmol but not 1 nmol) inhibited behavioral RIH and peroxiredoxin-3 acetylation. Moreover, hyperalgesia and peroxiredoxin-3 hyperacetylation were attenuated after the combination of artesunate (1 μg) and MPEP (1 nmol). Additionally, artesunate treatment reversed acute pain and peroxiredoxin-3 hyperacetylation following spinal exposure to DHPG. In conclusion, intrathecal injection of artesunate impairs RIH by down-regulating spinal mGluR5 expression and peroxiredoxin-3 hyperacetylation-mediated oxidative stress in rats., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Nano-carbon is often used as a tracer in thyroidectomy, to improve the accuracy of the operation. Remifentanil is the most commonly used anesthetic during thyroidectomy, but the use of remifentanil can sometimes cause patients with anesthesia hyperalgesia. Therefore, auxiliary anesthetics are often used in surgery to prevent remifentanil from causing anesthesia hyperalgesia. The purpose of this article is to explore the specific application effect of the fusion agent of hydromorphone and parecoxib sodium after thyroidectomy based on nano-carbon in the prevention of remifentanil-induced anesthesia hyperalgesia. Taking 60 patients who underwent thyroidectomy based on carbon nanotechnology in our hospital as the research object, the patients were divided into the parecoxib sodium group, hydromorphone control group and hydromorphone and parecoxib sodium fusion agent group. All patients were injected with remifentanil before surgery for general paralysis. Ten minutes before the end of the operation, the parecoxib sodium group was injected with quantitative parecoxib sodium, and the hydromorphone control group was injected with quantitative hydromorphone, hydromorphone and the parecoxib sodium fusion medicament group was injected with a quantitative combination of parecoxib sodium and hydromorphone. The patient's comfort, calmness, pain, adverse reactions and recovery time of consciousness were counted. The results of the study showed that the sedation score of the hydromorphone and parecoxib sodium fusion drug group was (15.8±1.5), the pain degree score was (1.9±0.5), lower than the other two groups, and the postoperative recovery time was (38±5.0) )min, lower than the other two groups. It can be seen that the use of a fusion agent of hydromorphone and parecoxib sodium after thyroidectomy based on nano-carbon is effective in preventing and reducing remifentanil-induced anesthesia hyperalgesia.

Objective: To explore the changes of entropy index and cerebral oxygen metabolism in the maintenance of remifentanil anesthesia and the predictive value of postoperative hyperalgesia., Methods: A total of 266 patients undergoing general anesthesia in our hospital from January 2020 to October 2021 were selected, and remifentanil was used to maintain anesthesia. The state entropy, reaction entropy, and cerebral oxygen metabolism indexes (cerebral oxygen uptake rate (CERO 2 ), arterial-venous blood oxygen difference (Da-jvO 2 )) of patients before induction of anesthesia, 15 minutes during the operation, and at the end of the operation were compared. The influencing factors of postoperative hyperalgesia were analyzed. The logistic regression model of postoperative hyperalgesia was established, and the value of entropy index and cerebral oxygen metabolism in predicting postoperative hyperalgesia was evaluated by drawing the receiver operating characteristic curve (ROC)., Results: The state entropy, response entropy, and CERO 2 at 30 min during the operation and at the end of the operation were lower than those before the induction of anesthesia, and Da-jvO 2 was higher than that before the induction of anesthesia ( P < 0.001). At the end of the operation, the state entropy, reaction entropy, and CERO 2 were higher than 30 minutes during the operation, and Da-jvO 2 was lower than 30 minutes during the operation ( P < 0.001). The dosage of remifentanil, reaction entropy, and CERO 2 at the end of the operation entered the logistic model. The AUC value of the reaction entropy and CERO 2 combined to predict postoperative hyperalgesia at the end of the operation was 0.851 greater than the reaction entropy at the end of the operation ( χ 2 = 3.847, P = 0.036), CERO 2 ( χ 2 = 2.589, P = 0.010) single index predictive value., Conclusion: The entropy index and cerebral oxygen metabolism in general anesthesia patients change with the progress and discontinuation of remifentanil maintenance anesthesia, and the combination of the two has a high predictive power in postoperative hyperalgesia risk assessment. When the reaction entropy > 54.23, CERO 2 > 34.14%, or the total dosage of remifentanil ≥ 30  μ g/kg at the end of the operation, we should be highly vigilant of the occurrence of postoperative hyperalgesia and postoperative analgesia management should be strengthened., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Tianhao Zhang and Fang Ma.)

Background: A clinical study indicated that infusion of dexmedetomidine without a loading dose administered intraoperatively provided a smooth and hemodynamically stable emergence and improved the quality of recovery with fewer postoperative side effects and reduced analgesic requirements. The objective was to determine whether administering remifentanil-propofol combined with dexmedetomidine during general anesthesia would decrease the incidence and severity of postoperative emergence agitation, anxiety, and depression without affecting cognitive dysfunction in elderly patients., Methods: A total of 120 elderly patients scheduled for ureteroscopic holmium laser lithotripsy were randomly allocated to the PR group and administered normal saline, and the PRD group was administered dexmedetomidine 0.4 μg kg -1 h -1 intravenously after the induction of anesthesia and stopped 30 min before the end of surgery. The primary outcome was the Mini-Mental State Examination score. The secondary outcomes were the Richmond Agitation Sedation, the State-Trait Anxiety Inventory, and the Zung Self-Rating Depression Scale scores; the memory span for Arabic numerals; the duration of surgery; and the time to spontaneous respiration, recovery, and extubation., Results: The MMSE scores were lower at T 1-2 in the two groups (P < 0.001). The dosage of propofol and remifentanil decreased more significantly in the PRD group than in the PR group (P < 0.001). Both the RASS scores and the incidence of emergence agitation (EA) in the PRD group were significantly lower than those in the PR group at t 1-3 (P < 0.001). Compared to the PR group, the ZSDS scores and STAI scores at T 1-2 were lower in the PRD group (P < 0.005). The number of the Arabic numbers that were accurately recalled from memory was lower at T 2 in the PR group than in the PRD group (P < 0.001)., Conclusion: Dexmedetomidine administration has no influence on postoperative cognitive dysfunction but could reduce both the dosage of remifentanil and propofol needed during ureteroscopic holmium laser lithotripsy and the incidence and severity of postoperative emergence agitation, anxiety, and depression in elderly patients., Trial Registration: Chinese Clinical Trial Registry ChiCTR1900021254 . Registered on 3 February 2019., (© 2022. The Author(s).)

Lateralized periodic discharges (LPDs) are a common electroencephalographic (EEG) pattern in the neurointensive care unit setting. LPDs are typically observed in association with acute structural lesions of the brain with different etiologies. There are no reports describing a link between the occurrence of LPDs and the administration of remifentanil. Remifentanil is a rapid-acting pure μ-opioid receptor agonist, which is indicated to provide analgesia and sedation in mechanically ventilated patients in intensive care units. We present a case of an 84-year-old man with neuroglycopenia who developed LPDs while sedated with remifentanil. We report, for the first time, a potential relationship between remifentanil and the induction of LPDs.

High-dose opioids induce hyperalgesia and tolerance, which negatively affects postoperative recovery. Prolonged surgery inevitably requires higher opioid doses. Ketamine reduces perioperative opioid consumption and prevents opioid-induced tolerance. However, its effects in cases of prolonged surgery remain unknown. This study aimed to evaluate the dose of intraoperative remifentanil, an ultrashort-acting µ-opioid agonist, administered after an intravenous ketamine bolus during prolonged head and neck surgery. This single-center, retrospective, observational study included 251 patients who underwent head and neck surgery (operation time ≥8 h) between January 2015 and December 2019. The participants were stratified into two groups: those who received an intravenous bolus of ketamine and those who did not (ketamine group and non-ketamine group, respectively). Propensity score-matching was used to match patients in a 1:1 ratio between the two groups, based on their covariates. The difference in intraoperative remifentanil dose administered between the two groups was assessed. After 1:1 propensity score-matching, 89 matched patients were selected from each group. The mean ± standard deviation dose of remifentanil administered was significantly lower in the ketamine group than in the non-ketamine group before (0.15±0.05 vs 0.17±0.05 µg/kg/min; P =0.01) and after matching (0.15±0.06 vs 0.17±0.05 µg/kg/min; P =0.03). In conclusion, intravenous ketamine administration may reduce the intraoperative dose of remifentanil required during prolonged head and neck surgery. However, further studies are required to evaluate the effect of this finding on enhanced recovery after surgery., Competing Interests: All authors declare that they have no conflicts of interest.

Objectives: To compare between 2 sedoanalgesia regimes, the time from withdrawal of the medication until the patient wakes up and until extubation., Methodology: Observational study on pediatric patients after elective surgery that needed mechanical ventilation for a period maximum to 72 h. We compared two independent groups of patients: group A: patients collected prospectively who received sedoanalgesia with propofof-remifentanil and group B: patients who received midazolam-fentanyl collected retrospectively by reviewing medical records and database of the unit. The main variables studied were: Age, weight, sex, interventions type, sedoanalgesia scales, drugs dosages, time from withdrawal of medication to awakening and extubation, and adverse effects., Results: We collected 82 patients, 43 in group A and 39 in group B. Age (arithmetical mean ± standard deviation of patients were 49 ± 65 months, weight 17 ± 16 kg. Mechanical ventilation medium time was 22 h (3-72), wake-up time from withdrawal after removing sedoanalgesia was of 11,8 ± 10,6 min group A and 137,3 ± 45 min group B (P < 0.001), extubation time after removing sedoanalgesia was of 24 ± 21 min group A and 230 ± 102 min group B (P < 0.001). Adverse effects were found in 10.5% of patients group A (7.9% agitation, 2.6% bradycardia), and 13% of patients group B (respiratrory depression after extubation) P = 0,572., Conclusions: Patients treated with propofol-remifentanil have significantly shorter times to wake up, extubation and withdrawal from mechanical ventilation after stopping the medication. In the midazolam-fentanyl group, respiratory depression was more frequent, although the percentage of adverse effects were similar in both groups. Both the combination of propofol-remifentanil and midazolam-fentanyl appear to be effective as a sedative-analgesic regimen for patients undergoing mechanical ventilation after surgery., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Background: The purpose of this study was to evaluate the efficacy and safety of sevoflurane-remifentanil (SR) vs propofol-remifentanil (PR) as inhalation anesthesia or total intravenous anesthesia in patients undergoing craniotomy, respectively., Methods: Electronic databases included PubMed, ScienceDirect, Embase, Cochrane library, CNKI, and Wanfang data were searched using suitable search items. Randomized clinical controlled trials comparing the combination of SR and PR as anesthetics for neurosurgery were included. The outcomes included wake-up time, spontaneous respiration time, extubation time, and safety., Results: Seventeen studies were included in this meta-analysis. There were no statistically significant differences in wake-up time (P = .25, standardized mean difference (SMD) = 0.29, 95% CI -0.20 to 0.77), extubation time (P = .1, SMD = 0.52, 95% CI -0.11 to 1.14) and spontaneous respiration time (P = .58, SMD = 0.43, 95% CI -1.07 to 1.93) when patients with SF and PF for anesthesia maintenance. Moreover, the changes of hemodynamic parameters are similar between the 2 groups. During anesthesia maintenance, SF could significantly increase the incidence of hypotension and brain edema than PF (P = .02, SMD = 1.68, 95% CI 1.07 to 2.62; P < .0001, SMD = 3.37, 95% CI 1.86 to 6.12), PF markedly promoted the incidence of hypertension (P = .001, SMD = 0.55, 95% CI 0.39 to 0.79). The postoperative adverse reactions were similar between the 2 groups (P > .05), but the incidence of postoperative nausea and vomiting proved to be higher in SF group (P < .0001, SMD = 2.12, 95% CI 1.47 to 3.07)., Conclusions: SR and PR as anesthetics in patients underwent craniotomy had similar effects, but PR was superior to SR in terms of safety of intraoperation and postoperation., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To explore the application of different doses of dexmedetomidine combined with general anesthesia in patients with traumatic tibiofibular fractures., Methods: A total of 120 patients with traumatic tibiofibular fractures treated in our hospital (January 2018-January 2021) were selected as the research subjects and equally grouped into group A, group B, group C, and group D according to the dosage of dexmedetomidine. Group B, group C, and group D were pumped with 0.3  μ g/kg, 0.5  μ g/kg, and 0.8  μ g/kg load doses of dexmedetomidine before anesthesia induction, with the same doses for maintenance during surgery. Group A was intravenously pumped with the same amount of normal saline and received tracheal intubation after anesthesia induction, with propofol and remifentanil to maintain general anesthesia during surgery., Results: No notable differences in general data were observed among the groups ( P  > 0.05). Ramsay sedation scores of all groups showed a downward trend after drug withdrawal. At 10 min, 30 min, and 60 min, the scores of groups C and D were markedly higher than those of groups A and B ( P  < 0.05), and the scores were higher in group D than those in group C ( P  < 0.05). The HR changes at each period were close between groups A and B ( P  > 0.05). The HRs at T1 and T2 in group C were slightly lower than those in group D ( P  > 0.05), and the HRs at T1 in groups A and B were remarkably higher than those in groups C and D, and were higher than those at T0 and T2 ( P  < 0.05). The SBP levels of all groups began to rise at T0, peaked at T1, and decreased to a lower level at T2 than that at T0. Moreover, the SBP levels of groups C and D at T1 and T2 were notably lower compared with groups A and B ( P  < 0.05). With a lower DBP level in group C than the other three groups at T1, the DBP levels were notably lower in groups C and D than those in groups A and B at T2 ( P  < 0.05). With no statistical difference in the MAP levels at T0 among the four groups ( P  > 0.05), the MAP levels in group A at T1 and T2 were obviously higher compared with groups C and D ( P  < 0.05). The extubation time in group A was notably longer than that that in groups B, C, and D ( P  < 0.05), with longer extubation time in group B than that in groups C and D ( P  < 0.05). The orientation recovery time in group D was markedly shorter than that in groups A, B, and C ( P  < 0.05). The incidence of cognitive dysfunction, chills, and restlessness in groups C and D was notably lower compared with groups A and B ( P  < 0.05), with a higher incidence of chills, intraoperative hypotension, and delayed awakening in group D than in group C ( P  < 0.05)., Conclusion: Dexmedetomidine at doses of 0.5  μ g/kg and 0.8  μ g/kg has a better effect in the maintenance of general anesthesia for patients with traumatic tibiofibular fractures, with faster orientation recovery, better recovery of postoperative cognitive function, and a lower incidence of adverse reactions. Dexmedetomidine at 0.5  μ g/kg is recommended in view of the increased risk of excessive sedation, chills, restlessness, and intraoperative hypotension in patients at 0.8  μ g/kg., Competing Interests: The authors declare no conflicts of interest.Jizheng Zhang and Xiaohua Sun contributed equally to this article., (Copyright © 2021 Jizheng Zhang et al.)

Background: Remifentanil-induced postoperative hyperalgesia is an intractable side effect of the clinical use of remifentanil, the mechanism of which remains obscure, especially in the peripheral nervous system. N-methyl-D-aspartate receptor (NMDAR) phosphorylation in dorsal root ganglion (DRG) plays a pronociceptive role in neuropathic pain. The contribution of the P2Y1 purinergic receptor (P2Y1R) in DRG to pain hypersensitivity derived from various origins and P2Y1R upregulation-induced NMDAR activation in neurons have also been uncovered. This study aimed to investigate whether P2Y1R participates in nociceptive processing in the DRG and spinal cord in remifentanil-induced postoperative hyperalgesia., Methods: Rats with remifentanil-induced postoperative hyperalgesia were intrathecally injected with NMDAR antagonist MK801 or P2Y1R antagonist MRS2179 at 10 min prior to remifentanil infusion. Mechanical allodynia, heat hyperalgesia, and cold hyperalgesia were measured at -24 h, 2 h, 6 h, 24 h, and 48 h following remifentanil infusion. The P2Y1R expression and NMDAR expression and phosphorylation in DRG ipsilateral to the incision were detected by Western blot and immunofluorescence., Results: Incision and remifentanil induced mechanical allodynia, heat hyperalgesia, and cold hyperalgesia accompanied by upregulated P2Y1R expression, increased NMDAR subunit NR1 expression and phosphorylation at Ser896, and NR2B expression and phosphorylation at Tyr1472 in DRG. Inhibition of NMDAR phosphorylation by MK801 effectively attenuated remifentanil-induced postoperative hyperalgesia. Furthermore, P2Y1R blockade by MRS2179 not only lessened remifentanil-evoked postoperative hypersensitivity to mechanical, heat, and cold stimuli, but also suppressed the increases in NR1 and NR2B expression and phosphorylation in DRG induced by incision and remifentanil., Conclusion: The process by which P2Y1R mediates NMDAR expression and phosphorylation represents a mechanism of remifentanil-induced postoperative hyperalgesia in the DRG and/or spinal cord., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Study Objective: The main objective of this study is to test the feasibility of the local anesthetic (LA) Mepivacaine 1% and sedation with Remifentanil as the primary anesthetic technique for the insertion of a peritoneal dialysis (PD) catheter, without the need to convert to general anesthesia., Methods: We analyzed 27 consecutive end-stage renal disease (ESRD) patients who underwent the placement of a peritoneal catheter at our center between March 2015 and January 2019. The procedures were all performed by a general or vascular surgeon, and the postoperative care and follow-up were all conducted by the same peritoneal dialysis team., Results: All of the 27 subjects successfully underwent the procedure without the need of conversion to general anesthesia. The catheter was deemed prone to usage in all patients and was found to be leak-proof in 100% of the patients., Conclusion: This study describes a safe and successful approach for insertion of a PD catheter by combined infiltration of the local anesthetic Mepivacaine 1% and sedation with Remifentanil. Hereby, ESRD patients can be treated without general anesthesia, while ensuring functionality of the PD catheter., Competing Interests: The authors have declared that no competing interests exist.