The Regulatory Effect of Remifentanil on JNK Signaling during Remission of Flap Ischemia-Reperfusion Injury.

BACKGROUND: The impact of remifentanil on hypogastric flap function following ischemia-reperfusion (I/R) injury remains largely unknown, limiting its potential clinical application in flap surgery. This study investigated the therapeutic effects of remifentanil on hypogastric flap I/R injury. METHODS: Aortic endothelial cells were extracted from the hypogastric flap I/R injury models established in-house using Sprague-Dawley rats, and were treated under hypoxic conditions. The cells were treated with 0.1, 1, 10 and 100 ng/mL remifentanil and 10 ng/mL anisomycin (the activator of c-Jun N-terminal kinase [JNK]). Histopathological changes and tumor necrosis factor alpha (TNF-α) content of the flaps were observed after hematoxylin-eosin staining and immunohistochemistry. Immunofluorescence, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and flow cytometry were employed for apoptosis evaluation. Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were utilized to assess the protein and gene expression levels of TNF receptor 1 (TNFR1), JNK1, phosphorylated (p)-JNK1, malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO) and TNF-α in the flaps and cells. RESULTS: The endothelial necrosis and cell apoptosis of rat flaps induced by I/R injury were ameliorated by remifentanil, and declining aortic endothelial cell viability and augmented apoptosis induced by hypoxia were reversed by remifentanil (10, 100 ng/mL) (p < 0.05). Remifentanil reversed the increased expressions of TNFR1, JNK1, p-JNK1, MDA and TNF-α induced by I/R injury or hypoxia in the flaps and cells (p < 0.05), and counteracted the decreased levels of NO and SOD induced by I/R injury in the flaps (p < 0.05). Anisomycin reversed the effects of remifentanil on suppressing TNFR1, JNK1 and p-JNK1 levels and apoptosis in the cells (p < 0.05). CONCLUSION: Remifentanil ameliorates cell apoptosis and vascular endothelial necrosis induced by I/R injury in the hypogastric flap, likely by downregulating the TNF-α/TNFR1 pathway and JNK1 signaling. These findings suggest that remifentanil may be a promising therapeutic agent for improving hypogastric flap survival in clinical settings.

The Impact of Different Anesthetics on the Distribution and Cytotoxic Function of NK Cell Subpopulations: An In Vitro Study.

Only some subpopulations of natural killer (NK) cells have cytotoxic functionality, and the effects of anesthetics on these subpopulations are unknown. This study aimed to evaluate the in vitro effects of various anesthetics, both alone and in combination, on the distribution and cytotoxic function of NK cells and their subpopulations. Peripheral blood mononuclear cells (PBMCs) from eight healthy volunteers were treated for 4 h in vitro with dexmedetomidine, remifentanil, lidocaine, propofol, sevoflurane, and combinations in clinically relevant concentrations or left untreated. Flow cytometry was used to quantify the percentage of sampled NK cells and evaluate their distribution (CD56brightCD16neg, CD56brightCD16dim, CD56dimCD16neg, CD56dimCD16bright, and CD56negCD16bright) and cytotoxicity (Granzyme B (GrzB) and perforin) of NK cell subpopulations. Although the percentage of total NK cells did not change following exposure to anesthesia, the most important cytotoxic subpopulation (CD56dimCD16bright NK cells) decreased after exposure to both propofol (-3.58%, p = 0.045) and sevoflurane (-16.10%, p = 0.008) alone, and most combinations, especially in combination with lidocaine (propofol with lidocaine (-9.66%, p = 0.002) and sevoflurane with lidocaine (-21.90%, p < 0.001)). Dexmedetomidine and remifentanil had no effect on CD56dimCD16bright NK cells. Furthermore, no anesthetic regimen or combination altered the expression of GrzB and perforin in NK cells or NK cell subpopulations. In short, propofol and sevoflurane suppressed the highly cytotoxic phenotype (CD56dimCD16bright) of NK cells, with those exposed to sevoflurane combinations showing greater reductions. Immunosuppression was intensified with the inclusion of lidocaine in the anesthetic regimen.

Effects of Propofol, Low and High Doses of Remimazolam on Hemodynamic and Inflammatory Response in Laparoscopic Surgery.

Background: This study explored the effects of different doses of remimazolam tosilate (RT) and propofol combined with remifentanil anesthesia on hemodynamic and inflammatory responses in patients undergoing laparoscopic surgery. Subjects and Methods: Ninety patients with a BMI of less than 35 kg/m², classified as ASA II-III and scheduled for laparoscopic surgery, were enrolled in this study. Patients were divided into three groups: low-dose RT group (A), high-dose RT group (B), and propofol group (C). The changes in hemodynamic indices such as SBP, DBP, HR, MAP, and inflammatory response indices such as IL-6, SAA, CRP, and PCT, along with extubation time and doses of sufentanil, remifentanil, urapidil, and phenylephrine, were compared among the three groups. Results: There were no statistically significant differences in extubation time, doses of sufentanil and remifentanil, or the usage rates and average doses of urapidil and phenylephrine between the three groups. The average dose of phenylephrine in group A was lower than in group B and group C, with a statistically significant difference. There were no statistically significant differences among the groups in SBP, DBP, HR, and MAP from T0 to T2, nor in IL-6, SAA, CRP, or PCT levels. Conclusion: Using RT for induction and maintenance of anesthesia in laparoscopic surgery ensures stable hemodynamic and inflammatory responses in patients. Low-dose RT may reduce the usage rate and dose of vasopressors such as phenylephrine during surgery.

Subanesthetic Dose of Esketamine Improves the Sedative and Analgesic Effects of Dexmedetomidine and Remifentanil in Liposuction Anesthesia: A Prospective, Double-Blinded, Randomized Controlled Trial.

Purpose: Esketamine have anesthetic and analgesic properties. This study aimed to observe the enhancing effect of subanesthetic doses of esketamine (0.15-0.3 mg/kg/h) with dexmedetomidine and remifentanil during anesthesia for liposuction surgery. Patients and Methods: A total of 155 subjects were randomized with a 1:1 ratio to Group E (esketamine-dexmedetomidine/remifentanil, n=78) or Group C (saline-dexmedetomidine/remifentanil group, n=77). The primary outcome was satisfaction of patient and surgical team with the procedure. The secondary outcomes were the postoperative Athens Insomnia Scale (AIS) and Hospital Anxiety and Depression Scale (HADS) scores, hemodynamic and respiratory changes, drug consumption, adverse event rates, and predictors associated with patient satisfaction. Results: Patient and surgical team satisfaction with the procedure was significantly higher in Group E than in Group C (4.7 ± 0.6 vs 4.2 ± 0.7, P < 0.001; 4.7 ± 0.5 vs 4.4 ± 0.7, P = 0.005). The postoperative AIS (4 [1, 6] vs 5 [2, 9], P = 0.012) and HADS-A (1 [0, 3] vs 2 [0, 6], P = 0.012) scores were significantly lower in Group E than in Group C. Hemodynamic and respiratory parameters were more stable in Group E than in Group C, with the lower opioids consumption of sufentanil (0 [0, 4] vs 5 [2.5, 7.7], P < 0.001) and remifentanil (700 [480, 900] vs 800 [500, 1200], P = 0.023) in Group E compared to Group C. On ordinal logistics regression, postoperative sleep quality (OR, 0.70; 95% CI, 0.62-0.79), anxiety level (OR, 0.77; 95% CI, 0.62-0.95) and recovery time in post-anesthesia care unit (PACU) (OR, 0.69; 95% CI, 0.56-0.98) were identified as significant predictors associated with patient satisfaction. Conclusion: A subanesthetic dose of esketamine (0.15-0.3 mg/kg/h) as an adjuvant can improves the sedative and analgesic effects of dexmedetomidine and remifentanil during anesthesia for liposuction surgery. Clinical Trial Registration: ChiCTR2400080363.

Impact of low-dose sevoflurane with propofol-based anaesthesia on motor-evoked potentials in infants: protocol for a single-centre randomised controlled study.

INTRODUCTION: Motor-evoked potentials (MEP) are widely used to mitigate the risk of nerve injury resulting from surgical manipulation. Infants are more susceptible to anaesthetics that suppress MEP because of the immaturity of their nervous structures. Current evidence of the impact of the interaction between a small dose of sevoflurane and propofol-based total intravenous anaesthesia (TIVA) on MEP in infants is controversial. This current study aims to evaluate the impact of the coadministration of low-dose sevoflurane with propofol-based TIVA on MEP in infants. METHODS AND ANALYSIS: A randomised controlled study will be conducted at a single tertiary care children's hospital in Japan between July 2024 and June 2029. Children between 35 and 87 weeks of postconceptual age undergoing spinal surgery requiring MEP under general anaesthesia will be enrolled in this study. The participants will be randomly allocated into two groups: propofol+remifentanil with (intervention group) or without (control group) low-dose sevoflurane (0.10-0.15 age-adjusted minimum alveolar concentration). MEP top-to-bottom amplitudes will be measured at two chronological points: T1 (first transcranial MEP (TcMEP) recording), T2 (second TcMEP recording) in the same patient. The primary and secondary endpoints will be a reduction in MEP amplitudes (T1-T2) in the right upper and lower extremities between the control and intervention groups, respectively. The sample size was calculated to be a total of 40 based on the preliminary data of 10 infants, which showed a 35% reduction in mean values of MEP amplitudes in the right adductor muscle (SD=31) with a 10% assumed dropout rate. ETHICS AND DISSEMINATION: The study protocol was approved by the Institutional Review Board of the Aichi Children's Health and Medical Center (2022058). The results will be reported in a peer-reviewed journal at the relevant academic conference. TRIAL REGISTRATION NUMBER: jRCT1041230094.

Remifentanil represses oxidative stress to relieve hepatic ischemia/reperfusion injury via regulating BACH1/PRDX1 axis.

BACKGROUND: Hepatic ischemia-reperfusion injury (HIRI) is a major cause of liver dysfunction after clinical liver surgery, which seriously affects the prognosis of patients. Remifentanil (RE) has been verified to attenuate HIRI. However, its therapeutic mechanism is still unclear. This study aimed to explore the protective mechanism of RE against HIRI. METHODS: A mouse HIRI model and an in vitro model of hypoxia/reoxygenation (H/R)-stimulated AML12 hepatocytes were established. Liver histopathological changes were evaluated by hematoxylin and eosin (HE) staining. Oxidative stress damage was assessed by malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) levels. Liver function was determined by serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH). and adenosine triphosphate (ATP) levels. Cell counting kit-8 (CCK-8) assessed cell viability. Apoptosis was measured by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) and flow cytometry. The levels of inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA) kits. The differentially expressed genes were evaluated by mRNA microarray analysis. Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR) were conducted to detect molecule expression. The binding of BTB and CNC homology 1 (BACH1) to peroxiredoxin 1 (PRDX1) was validated by chromatin immunoprecipitation (ChIP) and dual luciferase reporter assay. RESULTS: RE treatment improved liver function, and repressed oxidative stress damage and apoptosis in HIRI mice. Nine differentially expressed genes in the liver tissues of HIRI mice were selected by microarray analysis, among which BACH1 was down-regulated and PRDX1 was up-regulated after RE treatment. In addition, BACH1 directly bound to the promoter region of PRDX1 to inhibit its transcription and expression, which led to oxidative stress injury. BACH1 overexpression or PRDX1 silencing could counteract the beneficial effects of RE against HIRI. CONCLUSION: RE suppressed oxidative stress injury and inflammation via inactivation of the BACH1/PRDX1 axis, thereby ameliorating HIRI. Our findings enrich the understanding of the protective mechanisms of RE against HIRI, and provide novel evidence for its clinical application.

Influence of psychological factors and pain sensitivity on the efficacy of opioid-free anesthesia: A randomized clinical trial.

OBJECTIVE: This study aimed to investigate the effects of opioid-free anesthesia (OFA) in laparoscopic gastrectomy and identify the psychological factors that could influence the efficacy of OFA. METHOD: 120 patients undergoing laparoscopic gastrectomy were allocated to either the opioid-based anesthesia group (OA) (n = 60) or the OFA (n = 60) group. Remifentanil was administered to the OA group intraoperatively, whereas dexmedetomidine and lidocaine were administered to the OFA group. The interaction effect of the psychological factors on OFA was analyzed using the aligned rank transform for nonparametric factorial analyses. RESULTS: The opioid requirement for 24 h after surgery was lower in the OFA group than in the OA group (fentanyl equivalent dose 727 vs. 650 µg, p = 0.036). The effect of OFA was influenced by the pain catastrophizing scale (p = 0.041), temporal pain summation (p = 0.046), and pressure pain tolerance (p = 0.034). This indicates that patients with pain catastrophizing or high pain sensitivity significantly benefited from OFA, whereas patients without these characteristics did not. CONCLUSIONS: This study demonstrated that OFA with dexmedetomidine and lidocaine effectively reduced the postoperative 24-h opioid requirements following laparoscopic gastrectomy, which was modified by baseline pain catastrophizing and pain sensitivity. CLINICAL TRIAL REGISTRY: The study protocol was approved by the Institutional Review Board of Yonsei University Health System Gangnam Severance Hospital (#3-2021-0295) and registered at ClinicalTrials.gov (NCT05076903).

Using the nociception level index to compare the intraoperative antinociceptive effect of propofol and sevoflurane during clinical and experimental noxious stimulus in patients under general anesthesia.

STUDY: Propofol and sevoflurane are two anesthetic agents widely used to induce and maintain general anesthesia (GA). Their intrinsic antinociceptive properties remain unclear and are still debated. OBJECTIVE: To determine whether propofol presents stronger antinociceptive properties than sevoflurane using intraoperative clinical and experimental noxious stimulations and evaluating postoperative pain outcomes. DESIGN: A prospective randomized monocentric trial. SETTING: Perioperative care. PATIENTS: 60 adult patients with ASA status I to III who underwent elective abdominal laparoscopic surgery under GA were randomized either in propofol or sevoflurane group to induce and maintain GA. INTERVENTIONS: We used clinical and experimental noxious stimulations (intubation, tetanic stimulation) to assess the antinociceptive properties of propofol and sevoflurane in patients under GA and monitored using the NOL index, BIS index, heart rate, and mean arterial blood pressure. MEASUREMENTS: We measured the difference in the NOL index alterations after intubation and tetanic stimulation during either intravenous anesthesia (propofol) or inhaled anesthesia (sevoflurane). We also intraoperatively measured the NOL index and remifentanil consumption and recorded postoperative pain scores and opioid consumption in the post-anesthesia care unit. Intraoperative management was standardized by targeting similar values of depth of anesthesia (BIS index), hemodynamic (HR and MAP), NOL index values (below the threshold of 20), same multimodal analgesia and type of surgery. MAIN RESULTS: We found the antinociceptive properties of propofol and sevoflurane similar. The only minor difference was after tetanic stimulation: the delta NOL was higher in the sevoflurane group (39 ± 13 for the propofol group versus 47 ± 15 for sevoflurane; P = 0.04). Intraoperative and postoperative pain outcomes and opioid consumption were similar between groups. CONCLUSIONS: Despite a precise intraoperative experimental and clinical protocol using the NOL index, propofol does not provide a higher level of antinociception during anesthesia or analgesia after surgery when compared to sevoflurane. Anesthesiologists may prefer propofol over sevoflurane to reduce PONV or anesthesia-related pollution, but not for superior antinociceptive properties.

Acute nicotine administration reduces the efficacy of punishment in curbing remifentanil consumption in a seeking-taking chain schedule of reinforcement.

RATIONALE: Nicotine dependence is highly comorbid with opioid use disorders (OUDs). The use of nicotine-containing products increases the propensity to misuse prescription opioids and addressing both nicotine and opioid use simultaneously is more efficacious for treatment of OUDs than treating opioid use alone. OBJECTIVES: Given this extreme comorbidity, further elucidation of the effects of nicotine as a factor in promoting vulnerability to development of OUDs is needed. Here, we sought to further explore the effects of nicotine administration on operant self-administration of remifentanil (RMF), a fast-acting synthetic µ-opioid receptor agonist, using a heterogenous seeking-taking chain schedule of reinforcement in unpunished and punished conditions. METHODS: Male and female rats received nicotine (0.4 mg/kg) or saline prior to operant self-administration sessions. These sessions consisted of pressing a 'seeking' lever to gain access to a 'taking' lever that could be pressed for delivery of 3.2 µg/kg RMF. After acquisition, continued drug seeking/taking was punished through contingent delivery of foot-shock. RESULTS: Nicotine, relative to saline, increased RMF consumption. Furthermore, nicotine treatment resulted in significantly higher seeking responses and cycles completed, and this effect became more pronounced during punished sessions as nicotine-treated rats suppressed RMF seeking significantly less than controls. Nicotine treatment functionally reduced the efficacy of foot-shock punishment as a deterrent of opioid-seeking. CONCLUSIONS: Nicotine administration enhanced both appetitive and consummatory responding for RMF and engendered a punishment-insensitive phenotype for RMF that was less impacted by contingent administration of foot-shock punishment. These findings provide further support for the hypothesis that nicotine augments vulnerability for addiction-like behaviors for opioids.

Ciprofol alleviates remifentanil-induced hyperalgesia by regulating α2GABAARs, NR2B, and P-CaMKIIα levels in the spinal cord and hippocampus.

OBJECTIVES: Several studies have shown that propofol administration during surgery effectively attenuates remifentanil-induced hyperalgesia (RIH). Ciprofol, a novel intravenous sedative agent analogous to propofol, has not yet been proven efficacious in alleviating RIH. The present study aimed to investigate the effect of ciprofol on RIH and the possible mechanisms involved. METHODS: The RIH model was established by an infusion of remifentanil (1 µg·kg-1·min-1) 60 min in rats with incisional pain. Ciprofol (0.1, 0.25, and 0.4 mg·kg-1·min-1) was simultaneously infused to evaluate its effect on RIH. The antinociception of ciprofol was verified by measured paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). γ-aminobutyric acid type A receptor α2 subunit (α2GABAAR), N-methyl-d-aspartate receptor NR2B subunit (NR2B), calcium/calmodulin-dependent protein kinase II α (CaMKIIα), and phosphorylated CaMKIIα (P-CaMKIIα) in the spinal cord and hippocampus of rats were assessed by western blotting and immunohistochemistry. KEY FINDINGS: The results showed that ciprofol dose-dependently increased PWMT and PWTL values in RIH rats. Moreover, ciprofol upregulated α2GABAAR and downregulated NR2B and P-CaMKIIα in the rat spinal cord and hippocampus. CONCLUSIONS: Ciprofol alleviates RIH effectively, and the anti-hyperalgesic mechanisms may involve increasing α2GABAAR levels and decreasing NR2B and P-CaMKIIα levels in the spinal cord and hippocampus.

Predicting the optimal concentration of remifentanil for skull pin fixation with hemodynamic and analgesia nociception index monitoring.

Inadequate antinociception during skull pin fixation may cause hemodynamic instability in intracranial surgery. The optimal concentration of remifentanil to provide adequate antinociception and stable hemodynamics during skull pin fixation under analgesia nociception index monitoring is unknown. This study is to assess the 90% effective concentration of remifentanil for skull pin fixation under hemodynamic and analgesia nociception index monitoring. Twenty-six patients were enrolled for intracranial surgery, anesthesia was induced and maintained under total intravenous anesthesia using target-controlled infusion for remifentanil and propofol under analgesia nociception index and bispectral index monitoring. Skull pin fixation was performed at different effect-site concentrations of remifentanil required for Dixon's up-and-down method with a step size of 0.5 ng/ml under bispectral index 40-60. Inadequate antinociception is defined when either ANI < 30 or > 20% in hemodynamic changes from baseline (e.g. heart rate > 100 beats/min, or blood pressure > 180/100 mmHg) and the effect-site concentration of remifentanil is considered as failure. It is considered success as ANI > 30 and < 20% hemodynamic changes from baseline simultaneously. Seven pairs of failure/success were used for probit analysis. The 90% effective concentration of remifentanil for skull pin fixation with adequate antinociception and hemodynamic stability was 4.7 ng/ml.

Haemodynamic effects of remifentanil during induction of general anaesthesia with propofol. A randomised trial.

BACKGROUND: Remifentanil may have a dose-dependent haemodynamic effect during the induction of general anaesthesia combined with propofol. Our objective was to investigate whether systolic arterial blood pressure (SAP) was reduced to a greater extent when the remifentanil dose was increased. METHODS: This randomised, double-blind, dose-controlled study was conducted at the Day Surgery Unit of Haugesund Hospital, Norway. Ninety-nine healthy women scheduled for gynaecological surgery were randomly allocated in a 1:1:1 ratio to receive remifentanil induction with a low, medium or high dose corresponding to maximum effect-site concentrations (Ce) of 2, 4 and 8 ng/mL. The induction dose of propofol was 1.8 mg/kg, with a Ce of 2.9 µg/mL. Anaesthesia was induced using target-controlled infusion. After 150 s of sedation, a bolus of remifentanil and propofol was administered. Baseline was defined as 55-5 s before the bolus dose, and the total observation time was 450 s. We used beat-to-beat haemodynamic monitoring with LiDCOplus. The primary outcome variable was the maximum decrease in SAP within 5 min after bolus administration of remifentanil and propofol. Absolute and relative changes from baseline to minimal values and the area under the curve (AUC) were used as effect measures. Comparisons of groups were performed using analysis of variance (ANOVA). RESULTS: Median remifentanil doses were 0.75, 1.5 and 3.0 µg/kg in the low-, medium- and high-dose groups, respectively. The absolute changes (mean ± standard deviation) in SAP in the low-, medium- and high-dose groups of remifentanil were -39 ± 9.6 versus -43 ± 9.1, and -41 ± 10 mmHg, respectively. No difference (95% confidence interval) in the absolute change in SAP was observed between the groups (ANOVA, p = .29); medium versus low dose 3.7 (-2.0, 9.4) mmHg, and high versus medium dose -2.2 (-8.0; 3.5) mmHg. The relative changes from baseline to minimum SAP values were -30% versus -32% versus -32% (p = .52). The between-group differences in the AUC were not statistically significant. Relative changes in heart rate (-20% vs. -21% vs. -21%), stroke volume (-19% vs. -16% vs. -16%), cardiac output (-32% vs. -32% vs. -32%), systemic vascular resistance (-24% vs. -27% vs. -28%), and AUC were not statistically significant. CONCLUSION: This trial demonstrated major haemodynamic changes during the induction of anaesthesia with remifentanil and propofol. However, we did not observe any statistically significant differences between low, medium or high doses of remifentanil when using continuous invasive high-accuracy beat-to-beat monitoring.

Effect of fentanyl and remifentanil on neuron damage and oxidative stress during induction neurotoxicity.

Opioids can be used for medical and non-medical purposes. Chronic pain such as cancer, as well as the frequent use of such drugs in places such as operating rooms and intensive care units, and in non-medical areas like drug abuse the effects and side effects of these drugs need to be examined in more detail. For this purpose, the effects of fentanyl and remifentanil drugs on neuroinflammation, oxidative stress and cholinesterase metabolism were investigated. Neuron cells (CRL-10742) were used for the evaluation of the toxicity of fentanyl and remifentanil. MTT, PON1 activity and total thiol levels for its effect on oxidative stress, AChE and BChE activities for its effect on the cholinergic system, and TNF, IL-8 and IL-10 gene levels for its neuroinflammation effect were determined. The highest neurotoxic dose of fentanyl and remifentanil was determined as 10 µg/mL. It was observed that the rate of neuron cells in this dose has decreased by up to 61.80% and 56.89%, respectively. The IL-8 gene expression level in both opioids was down-regulated while IL 10 gene level was up-regulated in a dose-dependent manner compared to the control. In our results, the TNF gene expression level differs between the two opioids. In the fentanyl group, it was seen to be up-regulated in a dose-dependent manner compared to the control. Fentanyl and remifentanil showed an inhibitory effect against PON1, while remifentanil showed an increase in total thiol levels. PON1, BChE and total thiol activities showed similarity with MTT.

Effect of remifentanil on three effect-site concentrations of propofol and their relationship during electroencephalography at loss of response, at maximum alpha power, and at onset of burst suppression: a prospective randomized trial.

PURPOSE: The effect-site concentration (Ce) at loss of response (Ce-LOR) to propofol closely correlates both with Ce as electroencephalographic alpha power becomes highest (Ce-alpha) and with Ce at onset of burst suppression (BS) (Ce-OBS), when no opioids are administered. Co-administration of opioids dose-dependently decreases Ce-LOR. We investigated the influence of remifentanil on the relationship between these three Ces. METHODS: After receiving approval from our local ethical committee, with written informed consent, we enrolled 90 participants (ASA-PS I or II) who were scheduled for elective surgery. Participants were randomly assigned to three groups: constant remifentanil Ce 0 ng/ml (Remi_0); 1 ng/mL (Remi_1); and 2 ng/mL (Remi_2). We recorded both raw EEG and EEG-derived parameters on a computer. After reaching remifentanil equilibrium, we administered propofol using a target-controlled infusion pump such that propofol Ce increased to about 0.3 µg/mL/min. After determining Ce-LOR, we administered 0.6 mg/kg of rocuronium and started mask ventilation. The study protocol ended after observation of BS. RESULTS: Three participants were excluded. Ce-LOR in each group (Remi_0, Remi_1, Remi_2) was 2.00 ± 0.58 µg/mL, 1.43 ± 0.49 µg/mL, and 1.37 ± 0.42 µg/mL. Ce-alpha was 2.91 ± 0.63 µg/mL, 2.30 ± 0.41 µg/mL, and 2.12 ± 0.39 µg/mL. Ce-OBS was 3.80 ± 0.69 µg/mL, 3.25 ± 0.68 µg/mL, and 2.90 ± 0.57 µg/mL. In three other instances, Ce was decreased by remifentanil. Generalized linear model analysis revealed that remifentanil had no influence on the relationship between the three Ces. CONCLUSION: During propofol anesthesia, even low concentrations of remifentanil shifted concentration-related electroencephalographic changes.

Remifentanil improves left ventricular diastolic parameters in patients with impaired diastolic function: a prospective clinical study.

BACKGROUND: Left ventricular diastolic dysfunction has a significant impact on perioperative morbidity and mortality, and its incidence is high in elderly individuals. Anesthetic agents may impair diastolic function, which may increase the incidence of perioperative complications. The aim of this prospective, clinical, phase 4 study was to investigate the effects of remifentanil on left ventricle (LV) diastolic function in patients with diastolic dysfunction. The study was performed on 30 spontaneously breathing subjects (aged 60-80 years) with diastolic dysfunction. METHODS: Thirty patients (aged 60-80 years) with diastolic dysfunction scheduled for surgery were recruited between November 2019 and March 2023. Left ventricle function was evaluated once the intravenous remifentanil infusion reached a target-controlled concentration of 2 ng/ml with transthoracic echocardiography. Analysis of systolic function focused on left ventricular ejection fraction and mean mitral annular S velocity (Sm), whereas diastolic function focused on changes in transmitral peak flow (E), E/A, mitral septal and lateral e' waves, E/e' ratios and left atrial volume index following remifentanil infusion. RESULTS: Diastolic function measures of LV (mitral E/e', septal and lateral e' waves) statistically significantly improved (E/e' from 10.6 ± 2.9 cm.sn- 1 to 9.5 ± 2.2 cm.sn- 1; p = 0.006) following remifentanil infusion. Left atrial volume index decreased following remifentanil infusion without statistical significance (from 55 ± 14.4 ml.cm- 2 to 51.6 ± 13.3 ml.cm- 2; p = 0.1). Systolic function (ejection fraction and Sm) did not change following remifentanil infusion. CONCLUSIONS: Remifentanil improves left ventricular diastolic parameters in patients with preexisting diastolic dysfunction. Our study suggests that remifentanil at a plasma concentration of 2 ng.ml- 1 might be used safely in patients with left ventricular diastolic dysfunction.

The arousal effect of sugammadex reversal of neuromuscular blockade differs with anesthetic depth in propofol-remifentanil anesthesia: a randomized controlled trial.

Sugammadex reverses neuromuscular blockade by encapsulating steroidal neuromuscular blockers; therefore, it does not pharmacologically affect sedation levels. However, some clinicians avoid using it because of sudden unwanted acting out or patient arousal. Previous studies suggested sugammadex-induced awakening, but frontal muscle contraction after sugammadex administration compromised reliability of results obtained from EEG-based anesthesia depth monitoring tools like bispectral index (BIS). We hypothesized that sugammadex would affect patients' arousal depending on their baseline levels of sedation. We evaluated arousal signs after sugammadex administration with BIS between 25 - 35 and 45 - 55 under steady-state propofol-remifentanil anesthesia at the end of a surgery (n = 33 in each group). After sugammadex administration, twelve patients with a BIS of 45 - 55 showed clinical signs of awakening but none with a BIS of 25 - 35 (36.4% vs. 0%, P = 0.001). The distribution of the modified observer's assessment of alertness/sedation scale scores was also significantly different between the two groups (P < 0.001). Changes in the BIS were significantly greater in the BIS 45 - 55 than in the 25 - 35 group (median difference, 7; 95% CI 2 - 19, P = 0.002). Arousal after sugammadex was affected by patient sedation levels, and clinical signs of awakening appeared only in those with BIS 45 - 55. Unwanted arousal of the patient should be considered when using sugammadex under shallow anesthesia.Clinical trial registry number: Clinical Trial Registry of Korea ( https://cris.nih.go.kr ; Principal investigator: Jieae Kim; Registration number: KCT0006248; Date of first registration: 11/06/2021).

Efficacy of Isoflurane-Remifentanil versus Propofol-Remifentanil on Controlled Hypotension and Surgeon Satisfaction in Rhinoplasty: A Single-Blind Clinical Trial Study.

Background: Rhinoplasty is a complex but popular surgery in Iran. The main complications of the surgery are post-operative bleeding and nasal septal hematoma due to poor intra-operative controlled hypertension. This study aimed to compare the efficacy of isoflurane-remifentanil (I-R) versus propofol-remifentanil (P-R) to induce controlled hypotension and to assess surgeon satisfaction with each of these combinations during rhinoplasty. Methods: In 2020-2021, a single-blind clinical study was conducted on 98 patients aged 18-50 years undergoing rhinoplasty at Mother and Child Hospital (Shiraz, Iran). Patients were randomly divided into P-R (n=48) and I-R (n=50) groups. Changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) were assessed during surgery and in the recovery room. A questionnaire was used to evaluate the level of surgeon satisfaction. Data were analyzed using independent samples t test, Chi-square test, and repeated measures ANOVA with SPSS software. P<0.05 was considered statistically significant. Results: Five minutes after anesthesia induction, the P-R combination had a greater effect on reducing SBP (P=0.010), DBP (P=0.007), MAP (P=0.003), and HR (P=0.026) than I-R. However, from the 40th minute to the end of surgery and after 30 minutes of recovery, the I-R combination had a slightly better effect on blood pressure reduction than P-R. There was no difference in surgeon satisfaction with either of the two drug combinations. Conclusion: Both P-R and I-R combinations are recommended to induce hypotension during rhinoplasty. However, I-R is more effective than P-R in inducing the desired controlled hypotension.

Hemodynamic effects of a low versus a high dose of propofol during induction of anesthesia. A randomized trial.

BACKGROUND: Hypotension is common after anesthesia induction with propofol and is associated with increased morbidity. It is important to examine the effects of the proposed interventions to limit preventable hypotension, as suggested by the reduction in the dose of propofol. Our objective was to investigate whether a high dose of propofol is inferior to a low dose with respect to changes in systolic arterial blood pressure (SAP). METHODS: This randomized, double-blind, dose-controlled, non-inferiority study included 68 healthy women scheduled for gynecological surgery at the Day Surgery Unit, Haugesund Hospital, Norway. The patients were randomly allocated 1:1 to a low or high dose (1.4 mg/kg total body weight (TBW) versus 2.7 mg/kg TBW of propofol corresponding to maximal effect site concentrations (Ce) of 2.0 µg/mL versus 4.0 µg/mL. The dose of remifentanil was 1.9-2.0 µg/kg TBW, with maximal Ce of 5.0 ng/mL. The patients were observed for 450 s from the start of the infusions. The first 150 s was the sedation period, after which a bolus of propofol and remifentanil was administered. Baseline was defined as 55-5 s before the bolus doses. LiDCOplus was used for invasive beat-to-beat hemodynamic monitoring of changes in SAP, heart rate (HR), cardiac output (CO), stroke volume (SV), and systemic vascular resistance (SVR). A difference of 10 mmHg in the change in SAP was considered to be clinically important. RESULTS: The SAP change difference for low versus high dose was -2.9 mmHg (95% CI -9.0-3.1). The relative changes for low versus high dose were SAP -31% versus -36%, (p < .01); HR -24% versus -20%, (p = .09); SVR -20% versus -31%, (p < .001); SV -16% versus -20%, (p = .04); and CO -35% versus -32%, (p = .33). CONCLUSION: A high dose of propofol was not inferior to a low dose, and a reduction in the dose of propofol did not result in clinically important attenuation of major hemodynamic changes during induction in healthy women. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03861364, January 3, 2019.

Distinct Profiles of Desensitization of µ-Opioid Receptors Caused by Remifentanil or Fentanyl: In Vitro Assay with Cells and Three-Dimensional Structural Analyses.

Remifentanil (REM) and fentanyl (FEN) are commonly used analgesics that act by activating a µ-opioid receptor (MOR). Although optimal concentrations of REM can be easily maintained during surgery, it is sometimes switched to FEN for optimal pain regulation. However, standards for this switching protocol remain unclear. Opioid anesthetic efficacy is decided in part by MOR desensitization; thus, in this study, we investigated the desensitization profiles of REM and FEN to MOR. The efficacy and potency during the 1st administration of REM or FEN in activating the MOR were almost equal. Similarly, in ß arrestin recruitment, which determines desensitization processes, they showed no significant differences. In contrast, the 2nd administration of FEN resulted in a stronger MOR desensitization potency than that of REM, whereas REM showed a higher internalization potency than FEN. These results suggest that different ß arrestin-mediated signaling caused by FEN or REM led to their distinct desensitization and internalization processes. Our three-dimensional analysis, with in silico binding of REM and FEN to MOR models, highlighted that REM and FEN bound to similar but distinct sites of MOR and led to distinct ß arrestin-mediated profiles, suggesting that distinct binding profiles to MOR may alter ß arrestin activity, which accounts for MOR desensitization and internalization.

Remifentanil but not sufentanil induces cardioprotection in human ischemic heart muscle in vitro.

BACKGROUND: Previous studies on animal models have suggested that δ-opioid receptor (OR) signaling is the primary pathway responsible for opioids' cardioprotective effect. We hypothesize that the µ-OR's activation protects the human heart muscle. METHODS: We performed the experiments on muscular trabeculae obtained from the right atrial appendages of 104 consecutive patients subjected to coronary artery bypass surgery. Two trabeculae from each patient were studied simultaneously and exposed to 60 min of hypoxia with subsequent 60 min of reoxygenation. Remifentanil (5 µM or 50 µM) or sufentanil (40 µM or 400 µM) was used from the time of reoxygenation. Trabeculae contractility was assessed as the maximal amplitude of the contraction at baseline, after 60 min of hypoxia, during reoxygenation, and after norepinephrine application. RESULTS: During reperfusion, the application of remifentanil improved cardiomyocytes' function as compared to the control group (time from reperfusion: 15 min: 39.8% vs. 21.7%, p = 0.01; 30 min: 41.4% vs. 21.8%, p = 0.01; 60 min: 42.7% vs. 26.9%, p = 0.04; after norepinephrine: 64.7% vs. 43.2%, p = 0.03). The application of sufentanil did not influence cardiomyocyte function as can be seen when comparing the results of the experimental and control group. CONCLUSIONS: Remifentanil, but not sufentanil, induces a cardioprotective effect on human right atria muscle in in vitro conditions, manifested as the increased amplitude of their contraction during reperfusion after 60 min of ischemia.