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The quality of recovery (QoR) of remimazolam-based and propofol-based total intravenous anesthesia was compared as measured by QoR-15 scores. A prospective, double-blind, randomized controlled, non-inferiority trial. An operating room, a post-anesthesia care unit (PACU), and a hospital ward. Female patients (n = 140; 20–65 years) scheduled for open thyroidectomy were enrolled and randomly assigned to the remimazolam or propofol group. 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. 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. 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. 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. •Evidence regarding quality of recovery after remimazolam-based total intravenous anesthesia has been limited.•Remimazolam-based total intravenous anesthesia was explored in female patients undergoing open thyroidectomy.•Remimazolam-based total intravenous anesthesia demonstrated similar quality of recovery to propofol.•Hypotensive incidence at cessation of anesthetics was lower in patients administered with remimazolam compared to propofol.•Remimazolam-based total intravenous anesthesia was associated with reduced pain intensity and analgesic requirement.

To improve perioperative pain management, several interventions have been suggested for the prevention of increased pain sensitivity caused by opioids (called opioid-induced hyperalgesia). It is currently unclear which intervention is the most effective or appropriate in preventing opioid-induced hyperalgesia. Remifentanil is the most investigated opioid causing opioid-induced hyperalgesia. Thus, to guide future research, we conducted a systematic review and a network meta-analysis of preclinical trials investigating pharmacological interventions for remifentanil-induced hyperalgesia. To identify relevant articles, electronic database searches were conducted in Embase, PubMed, Web of Science, and Google Scholar. Study characteristics were extracted, and the risk of bias was evaluated. Studies were included in the network meta-analysis if they shared similar characteristics with at least one other study. The interventions were ranked based on P-scores. Overall, the 62 eligible trials tested 86 individual interventions and 6 combination interventions. Thirty-five studies eligible in the network meta-analysis formed five groups which were further divided into subgroups based on the quantitative sensory tests used. The best-ranked interventions within the subgroups were Anxa12-26, MRS2179, salicylaldehyde isonicotinoyl hydrazone (SIH), ANA-12, TDZD-8, ketamine, dexmedetomidine, JWH015, and the combination of KN93 and ketamine. The current literature is too heterogeneous to produce a clear answer on which intervention is the most effective in preventing remifentanil-induced hyperalgesia. Future research in this field should prioritise finding the most effective intervention over testing the efficacy of new options. The results of our work can be used in planning which comparisons should be included in new trials.

Monitoring the nociception/antinociception balance for analgesic guidance during general anesthesia may improve the quality of anesthesia. The University Hospital of Lille (France) has developed an expert software system for automatic remifentanil administration based on the continuous monitoring of the Analgesia Nociception Index (MDoloris, France). We assessed the clinical efficacy and safety of the ANI-REMI-LOOP \"expert-system software\" during burn surgery in a monocentric randomized controlled trial. The trial was approved by the French Ethics Committee, and all patients gave written informed consent. From 2018 to 2022, 52 adults were randomized into two groups: manual remifentanil infusion (standard practice) or automatic remifentanil infusion (expert-system software) during BIS-guided propofol anesthesia at the burn center of the hospital. In the standard practice group, remifentanil administration was based on Minto's model and guided by the analgesia nociception index. In both groups, propofol was administered based on Schnider's model and guided by the BiSpectral Index (Covidien). The primary endpoint was the cumulative remifentanil dose administered during anesthesia and secondary endpoints were related to the clinical safety of automatic remifentanil administration with the incidence and duration of hypotension, bradycardia, hypertension or tachycardia related to nociception. After anesthesia, the endpoints were pain and analgesic requirements during 2 hours. A p value < 0.05 was considered statistically significant. Data are presented as median [1st to 3rd quartile]. The cumulative remifentanil dose was significantly lower in the automatic group 0.125 µg.kg-1.min-1 [0.106 to 0.149] vs. 0.152 µg.kg-1.min-1 [0.137 to 0.237], p = 0.004), and the cumulative proportion of time with hemodynamic impairment or reactivity was significantly lower in the expert-system automatic group 4.2% [2.5 to 5.7] vs. 19.4% [6.9 to 59.9], p = 0.010). There were no safety issues, and pain and analgesic requirements were similar in both groups after surgery. Automatic remifentanil administration demonstrated good clinical performances during propofol anesthesia for burn surgery. It is likely that these results can be extrapolated to any surgical setting under general anesthesia, but this needs to be tested with further randomized clinical trials.

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.

Remimazolam's benefits for patients undergoing painless flexible fiberoptic bronchoscopy remain uncertain. We aimed to compare the efficacy and safety of remimazolam and dexmedetomidine in flexible fiberoptic bronchoscopy (FFB). Randomized controlled trial. University hospital. Between April 2021 and September 2022, patients undergoing painless flexible fiberoptic bronchoscopy were recruited. The patients were randomly assigned with a 1:1 ratio to remimazolam-remifentanil group (RR group) or dexmedetomidine-remifentanil group (DR group). The primary outcome was the procedure interruption rate during bronchoscopy. Secondary outcomes were hemodynamic changes, resuscitation time, rescue medication usage rate and dose, satisfaction scores of patients and bronchoscopists, operation-related complications, and adverse events. A total of 363 patients were included for final analysis. The interruption rates of bronchoscopy were 8.2 % in the RR group and 39.2 % in the DR group (P < 0.05). The rescue medication usage rate (4.4 % vs. 38.7 %, P < 0.05) and dose (1.51 ± 8.15 mg vs. 13.17 ± 18.86 mg, P < 0.05) were lower in the RR group compared with the DR group. The incidence of oxygen desaturation was significantly lower in the RR group than in the DR group (14.3 % vs. 44.2 %, P < 0.05). Hemodynamic changes in patients in the DR group were significant, with longer recovery time and lower satisfaction scores for both inpatients and bronchoscopists (P < 0.05), compared with the RR group. However, there were no significant differences between groups in terms of operation-related complications (P > 0.05) except for postoperative dizziness, which was more common in the DR group (P < 0.05). Remimazolam is effective and safe in painless flexible fiberoptic bronchoscopy. It allows a lower procedure interruption rate and incidence of oxygen desaturation, providing better hemodynamic stability compared to dexmedetomidine. •Remimazolam, an ultra-short-acting benzodiazepine, induced better sedation during bronchoscopy than dexmedetomidine.•Remimazolam had a better safety profile than that of dexmedetomidine.•Remimazolam anesthesia had higher bronchoscopist and patient satisfaction score.

Remifentanil, a widely used ultra-short-acting μ-opioid receptor agonist in clinical anesthesia, is strongly associated with postoperative hyperalgesia (remifentanil-induced hyperalgesia, RIH), posing significant challenges to postoperative pain management. RIH is characterized by an abnormally heightened pain perception following opioid withdrawal, and its underlying mechanisms are complex and multifactorial. Current research highlights the roles of central sensitization, peripheral sensitization, and multiple interacting molecular pathways. These include NMDA receptor activation, glial cell activation, neuroinflammation, disinhibition of inhibitory neurotransmission, and dysfunction of the descending pain modulation system. Additionally, alterations in ion channel expression, synaptic plasticity enhancement, and peripheral responses to inflammatory mediators contribute critically to RIH development. Individual factors such as age, sex, genetic polymorphisms, and surgical type significantly influence the risk of RIH. Although substantial progress has been made in elucidating the molecular mechanisms of RIH, a unified theoretical framework and effective clinical strategies remain lacking. Future studies should emphasize multi-omics approaches and clinically relevant experimental models to uncover key regulatory targets and provide a theoretical basis for individualized analgesic interventions.

We conducted a non-inferiority study to assess the postoperative quality of recovery (QoR) in elderly patients receiving ciprofol or propofol total intravenous anesthersia(TIVA)after elective laparoscopic major abdominal surgery, with QoR-15 scores as the main measure. A prospective, double-blind, randomized non-inferiority trial was conducted in the theater, post-anesthesia care unit (PACU), and the ward. 144 elderly patients (age ≥ 65 years) were randomly assigned to either the ciprofol group or the propofol group. The ciprofol group received continuous infusion of ciprofol with remifentanil, and the propofol group received infusion of propofol with remifentanil. The primary outcome was the QoR-15 on the first postoperative day (POD1), assessed in both intention-to-treat and per-protocol populations, with the mean difference between groups compared to a non-inferiority threshold of −8. Additional assessments included QoR-15 scores on POD2, 3, and 5 for both analysis sets. Other evaluated perioperative value factors included hemodynamic parameters and injection discomfort in the intention-to-treat analysis. A linear mixed model was utilized to examine the impact of group-time interactions on hemodynamic data and QoR-15. The QoR-15 scores on POD1 in the ciprofol group were non-inferior to those in the propofol group both in intention-to-treat set (mean [95 %CI], 95.9[93.7–98.2] vs. 95.6 [93.3–97.8]; mean difference [95 % CI], 0.4 [−2.8–3.5]; P<0.001 for noninferiority) and per-protocol set (mean [95 %CI], 96.7 [94.4–99.0] vs. 95.7 [93.4–98.0]; mean difference [95 % CI], 1.0 [−2.2–4.3]; P<0.001 for noninferiority). Comparable outcomes were noted on postoperative days 2, 3, and 5 following the procedure in both analysis sets. Additionally: compared with propofol group, the occurrence of injection pain was lower (2.8 % vs. 27.8 %, P < 0.001); the hypotension was less frequent (33.3 % vs. 54.2 %, P = 0.012); the bradycardia was more common (38.9 % vs. 23.6 %, P = 0.048). Ciprofol is not inferior to propofol in QoR. Ciprofol can be suitably administered to elderly patients undergoing elective laparoscopic major abdominal surgery. •Ciprofol is a novel intravenous anesthetic agent.•Ciprofol offers a comparable quality of recovery to propofol, with reduced injection pain, more stable intraoperative hemodynamics.•For elderly patients with cardiovascular diseases undergoing major laparoscopic surgery, ciprofol may be preferable to propofol.

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.

Background Pain is a risk factor for postpartum depression. This study aimed to determine the relationship between remifentanil analgesia and postpartum depression, as well as the birth experience among Iranian women. Methods This observational study was conducted on 200 mothers who underwent vaginal birth at Taleghani Hospital in Tabriz, Iran, in 2023-4. The Edinburgh Postnatal Depression Scale and the Childbirth Experience Questionnaire were used to assess the outcomes. To compare the childbirth experience and postpartum depression between the exposure group (receiving remifentanil) and the non-exposure group, independent t-tests and Mann-Whitney U tests were employed, respectively. Results The mean postpartum depression score in the remifentanil analgesia group was statistically significantly lower than that in the non-analgesia group ( p  = 0.002). The mean total childbirth experience score in the exposure group was statistically significantly higher than in the non-exposure group ( p  < 0.001). Additionally, a comparison of the subdomains of childbirth experience between the two groups showed that the mean scores for own capacity ( p  < 0.001), perceived safety ( p  < 0.001), and participation ( p  < 0.001) were statistically significantly higher in the remifentanil group compared to the non-analgesia group. However, there was no statistically significant difference between the two groups regarding the professional support subdomain ( p  = 0.434). Conclusion These findings underscore the significance of using remifentanil analgesia as a potential approach for preventing postpartum depression and creating a positive childbirth experience. It is recommended that clinical trials be conducted to obtain more precise results.

Opioids, which are widely used during surgery in perioperative settings, may cause hyperalgesia, especially when the opioid employed is remifentanil. Opioid-induced hyperalgesia may increase the length of a patient's hospital stay and negatively affect enhanced recovery after surgery and the patient's prognosis. Currently, there is no consensus on treatment strategies for remifentanil-induced postoperative hyperalgesia (RIPH). This study aimed to test the hypothesis that upregulation of lipocalin-2 (LCN2) in the anterior cingulate cortex (ACC) contributes to RIPH. A controlled animal study. A university laboratory. The RIPH mouse model was established through the subcutaneous infusion of remifentanil in mice undergoing plantar incision surgery. The von Frey test and the Hargreaves test were used to measure the pain threshold. By combining RNA sequencing, Western blotting, in vivo pharmacology, and the construction of adeno-associated virus vectors that modulated the expression level of LCN2 specifically, the role of LCN2 in the occurrence of RIPH in mice was explored. Compared to the mice that were subjected to the combination of incisions and saline (inci + saline), mice subjected to incisions and remifentanil (inci + remi) did not experience a significant reduction in the mechanical pain threshold of their ipsilateral hind paws. The mechanical pain threshold of the contralateral hind paws of the inci + remi mice was significantly reduced compared to those of the inci + saline mice. According to transcriptome analysis, LCN2 expression was significantly upregulated in RIPH-model mice. Furthermore, the Western blotting analysis also showed a significant increase in the level of LCN2 in the ipsilateral ACC of RIPH-model mice. An intra-anterior cingulate cortex injection of LCN2 mAb could attenuate hyperalgesia in mice. Knockdown of LCN2 expression in the ACC significantly alleviated mechanical hyperalgesia in mice. Additionally, the overexpression of LCN2 in the ACC could directly induce mechanical hyperalgesia without affecting thermal nociception. Future research needs to explore more potential mechanisms of affecting pain sensitivity through LCN2 upregulation. Our results demonstrated that the upregulation of LCN2 in the ACC plays a crucial role in the occurrence of RIPH, suggesting that LCN2 potentially be a therapeutic target for alleviating RIPH.