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Remimazolam was derived from its parent compound by adding an ester linkage into its structure so that the drug becomes a substrate for ester metabolism. As a result, it undergoes organ-independent ester hydrolysis, although the clinical benefits in terms of shorter recovery are not uniformly observed in clinical practice. Remimazolam is mainly tested in procedural sedation. In comparison to propofol, the current gold standard for procedural sedation, its proposed attractiveness is shorter wake-up times and a clear-headed recovery. Its clear advantages over propofol are better hemodynamic stability, lack of pain on injection and availability of a reversal agent in the form of flumazenil. Data on patient and proceduralist satisfaction are lacking. Remimazolam is also used for induction and maintenance of general anesthesia in Japan (where it is approved for this purpose). In this scenario, it is not clear if it can achieve the same degree of lack of recall as propofol. The use of remimazolam in obstetrics, pediatrics and high-risk populations is an emerging area. [ABSTRACT FROM AUTHOR]

Background: Opioid-induced rigidity is typically observed during rapid administration of fentanyl. Herein, we present a case in which rigidity occurred after reversal of rocuronium during emergence from anesthesia. Case presentation: A 73-year-old man underwent video-assisted partial lung resection. General anesthesia was induced with propofol, remimazolam, remifentanil, and rocuronium. Fentanyl was administered early during anesthesia. The surgery was completed without complications, and sugammadex sodium was administered for rocuronium reversal. The patient became agitated, but spontaneous breathing was maintained; therefore, the intratracheal tube was removed after the administration of flumazenil. The patient developed stiffness in the neck and jaw muscles along with remarkable skeletal muscle contractions. Dramatic improvement was observed immediately after administration of naloxone. Conclusions: Even as the simulated effect site concentration of fentanyl decreases during anesthesia emergence, opioid-induced rigidity may still occur. Rapid reversal of remimazolam by flumazenil might have contributed to the rigidity in this case. [ABSTRACT FROM AUTHOR]

Introduction: Clonazolam is a designer benzodiazepine that can be purchased illicitly on the internet. The use of designer benzodiazepines is increasing in both the United States and abroad, and patients may present to the emergency department (ED) after intentional or non-intentional overdose.Case report: This case report describes a patient who presented to a community ED after an intentional overdose on liquid clonazolam and was successfully treated with flumazenil.Conclusion: Since the pharmacologic action of clonazolam is similar to benzodiazepines, the sedative-hypnotic effect can be reversed with flumazenil, a benzodiazepine antagonist.

Lijuan Zhang,1 Zhe Wang,2 Yingge Liu,1 Xiaobao Zhang,1 Yong Wu1 1Department of Anesthesiology, Lianyungang Clinical College of Nanjing Medical University, Lianyungang, Jiangsu, People’s Republic of China; 2Department of Anesthesiology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, People’s Republic of ChinaCorrespondence: Yong Wu, Department of Anesthesiology, Lianyungang Clinical College of Nanjing Medical University, No. 6 East Zhenhua Road, Lianyungang, Jiangsu, 222061, People’s Republic of China, Tel +8618961325621, Email 18961325621@163.comPurpose: Remimazolam tosilate is a novel ultrafast-acting benzodiazepine that has a rapid emergence even after continuous infusion when using flumazenil. So far, relatively few articles are still focusing on the quality of recovery after general anesthesia with remimazolam, especially in day surgery. This study aimed to compare the early postoperative quality of recovery of remimazolam tosilate with flumazenil and propofol in patients undergoing day surgery.Patients and Methods: 137 patients scheduled for day surgery were randomly divided into the remimazolam tosilate or propofol group. The primary endpoint was the incidence of overall recovery assessed with the early postoperative quality of recovery scale (PostopQRS) on postoperative day 1 (POD 1). The Richmond Agitation-Sedation Scale (RASS) scores in the post-anesthesia care unit (PACU), extubation time, postoperative recovery profiles, and perioperative data were documented. Any adverse events were recorded.Results: The incidence of overall recovery on POD1 was 47.7% in the remimazolam tosilate group and 65.1% in the propofol group (odds ratio, 0.52; 95% confidence interval (CI) 0.26 to 1.06; P = 0.072). In general, the overall recovery of the PostopQRS increased over time, and its interaction between time and group was significant (P = 0.003). Among the five dimensions of PostopQRS, there exist statistical differences between groups including emotional state and cognitive recovery. Upon arrival at the PACU, the remimazolam group was more sedated and took longer to recover to a RASS score similar to propofol. The frequency of application of vasoactive drugs during anesthesia was similar in both groups (P = 0.119). Despite rapid emergence with remimazolam after flumazenil reversal, re-sedation (10.8%) or somnolence (60%) in the PACU was observed, and the length of PACU stay in patients treated with remimazolam tosilate was longer than that of the propofol (35 min vs 30 min, P< 0.001).Conclusion: General anesthesia with remimazolam tosilate in conjunction with flumazenil reversal permits rapid recovery of consciousness in day surgery, but there was a notable occurrence of re-sedation or somnolence observed in PACU.Keywords: remimazolam tosilate, flumazenil, propofol, day surgery, quality of recovery

Introduction: In the present study, anticonvulsant effects of aqueous extract (AE), hydro-alcoholic crude extract (HE), and its fractions (F-CHCl3, F-EtOAc, F-MeOH) of Paeonia daurica subsp. macrophylla (P. daurica ssp. macrophylla) root examined by using a pentylenetetrazol-induced model (PTZ) on mice. Methods: HE and its fractions as well as AE, in concentrations of (100, 200 and 400 mg/kg), valproate (Val) (100 and 200 mg/kg), and saline (negative control) (10 mg/kg) were injected intraperitoneally (i.p.) 30 min before PTZ (80 mg/kg, i.p.). The time taken before the onset of myoclonic convulsions (MC), MC duration, time taken before the onset of generalized tonic-clonic seizures (GTCS), the duration of GTCS, and the percentage of GTCS and mortality protection recorded. The plant's anticonvulsant mechanisms were assessed using flumazenil (5 mg/kg, i.p.) before AE (100, 200, and 400 mg/kg, i.p.) injection. GraphPad Prism software was used to compare the differences between various treatment groups with one-way analysis of variance (ANOVA) followed by Tukey–Krammer multiple comparison tests. Results: All the plant samples except F-EtOAc significantly delayed the onset and decreased the duration of PTZ-induced MCS and GTCS, and significantly reduced the GTCS and mortality rate. Pretreatment with flumazenil diminished the significant anticonvulsant effects of AE against PTZ-induced seizures. Conclusions: It can report that extract of P. daurica ssp. macrophylla might be a helpful guide for future studies in the treatment of epilepsy. Resumen: Introducción: Epilepsia es el término usado para un grupo de trastornos caracterizado por las convulsiones espontáneas recurrentes. Un estudio enfocado en los productos naturales de los recursos tradicionales ofrece ventajas significativas que se están utilizando de manera más amplia en modelos animales de epilepsia y candidatos a mayor desarrollo clínico y sus fracciones (F-CHCl3, F-EtOAc, F-MeOH) de Paeonia daurica subsp. macrophylla (P. daurica ssp. macrophylla) raíz examinada utilizando un modelo inducido por pentilentetrazol (PTZ) en ratones. Métodos: La maceración dinámica utilizada para extraer HE de la planta y técnica de cromatografía en columna de sílice utilizada para obtener F-CHCl3, F-EtOAc, así como fracciones de F-MeOH. La extracción de raíces secas se utilizó con agua destilada y se provocó AE. Las muestras de plantas (100, 200 y 400 mg/kg), valproato (Val) (100 y 200 mg/kg) y suero (control negativo) se inyectaron por vía intraperitoneal (ip) 30 min antes de PTZ (80 mg/kg, ip). El tiempo transcurrido antes del comienzo de convulsiones mioclónicas (MC), duración de las MC, tiempo transcurrido antes del comienzo de convulsiones tónico-clónicas generalizadas (GTCS), la duración de GTCS, así como el porcentaje de GTCS y protección contra la mortalidad registrada. Los mecanismos anticonvulsivos de planta fueron evaluados mediante el uso de flumazenil (5 mg/kg, ip) antes de AE (100, 200 y 400 mg/kg, ip) inyección. Se utilizaba el software GraphPad Prism® comparando las diferencias entre varios grupos de tratamiento con un análisis unilateral de variación (ANOVA) seguido por las pruebas de comparación múltiple de Tukey's Krammer. Resultados: Todas las muestras de plantas, excepto F-EtOAc, retrasaron de manera considerable el inicio, y disminuyeron la duración de PTZ inducidos por MCS y GTCS, y redujo significativamente el GTCS, así como la tasa de mortalidad. El tratamiento previo con flumazenil disminuyó los efectos anticonvulsivos importantes AE contra convulsiones inducidas por PTZ. Conclusiones: Puede concluirse que el extracto de P. daurica ssp. macrophylla podría ser útil en el tratamiento de la epilepsia en humanos.

Abstract Background General anesthesia is often necessary for dental treatment of outpatients with mental disabilities. Rapid recovery and effective management of postoperative nausea and vomiting (PONV) are critical for outpatients. This study aimed to investigate the effect of transitioning from propofol to remimazolam with flumazenil reversal administered toward the end of surgery during propofol-based total intravenous anesthesia (TIVA) on recovery. Methods Adults with mental disabilities scheduled to undergo dental treatment were randomly assigned to receive either propofol-based TIVA (Group P) or propofol-remimazolam-based TIVA with flumazenil reversal (Group PR). Propofol was replaced with remimazolam 1 h before the end of surgery in Group PR; moreover, 0.5 mg of flumazenil was administered after the neuromuscular blockade reversal agent. The primary outcome was the duration of stay in the post-anesthesia care unit (PACU). The secondary outcomes included time to eye-opening, time to extubation, occurrence of PONV, and quality of recovery. Results Fifty-four patients were included in this study. The duration of stay in the PACU in Group PR was significantly shorter than that in Group P (mean difference, 8.7 min; confidence interval [95% CI], 3.3–14.2; P = 0.002). Group PR exhibited a shorter time to eye opening (mean difference, 5.4 min; 95% CI, 3.3–8.1; P

We report that diazepam binding inhibitor (DBI) is a glial messenger mediating crosstalk between satellite glial cells (SGCs) and sensory neurons in the dorsal root ganglion (DRG). DBI is highly expressed in SGCs of mice, rats, and humans, but not in sensory neurons or most other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without major effects on other sensory modalities. In vivo overexpression of DBI in SGCs reduces sensitivity to mechanical stimulation and alleviates mechanical allodynia in neuropathic and inflammatory pain models. We further show that DBI acts as an unconventional agonist and positive allosteric modulator at the neuronal [GABA.sub.A] receptors, particularly strongly affecting those with a high-affinity benzodiazepine binding site. Such receptors are selectively expressed by a subpopulation of mechanosensitive DRG neurons, and these are also more enwrapped with DBI-expressing glia, as compared with other DRG neurons, suggesting a mechanism for a specific effect of DBI on mechanosensation. These findings identified a communication mechanism between peripheral neurons and SGCs. This communication modulates pain signaling and can be targeted therapeutically., Introduction Despite remarkable progress in our understanding of the fundamental biology of pain, current therapies for chronic pain are often inadequate and prone to serious side effects within the central [...]

Background: GABA, a key inhibitory neurotransmitter, has synaptic and extrasynaptic receptors on the postsynaptic neuron. Background GABA, which spills over from the synaptic cleft, acts on extrasynaptic delta subunit containing GABAA receptors. The role of extrasynaptic GABAergic input in migraine is unknown. We investigated the susceptibility to valid migraine-provoking substances with clinically relevant behavioral readouts in Genetic Absence Epilepsy of Rats Strasbourg (GAERS), in which the GABAergic tonus was altered. Subsequently, we screened relevant GABAergic mechanisms in Wistar rats by pharmacological means to identify the mechanisms. Methods: Wistar and GAERS rats were administered nitroglycerin (10 mg/kg) or levcromakalim (1 mg/kg). Mechanical allodynia and photophobia were assessed using von Frey monofilaments and a dark-light box. Effects of GAT-1 blocker tiagabine (5 mg/kg), GABAB receptor agonist baclofen (2 mg/kg), synaptic GABAA receptor agonist diazepam (1 mg/kg), extrasynaptic GABAA receptor agonists gaboxadol (4 mg/kg), and muscimol (0.75 mg/kg), T-type calcium channel blocker ethosuximide (100 mg/kg) or synaptic GABAA receptor antagonist flumazenil (15 mg/kg) on levcromakalim-induced migraine phenotype were screened. Results: Unlike Wistar rats, GAERS exhibited no reduction in mechanical pain thresholds or light aversion following nitroglycerin or levcromakalim injection. Ethosuximide did not reverse the resistant phenotype in GAERS, excluding the role of T-type calcium channel dysfunction in this phenomenon. Tiagabine prevented levcromakalim-induced mechanical allodynia in Wistar rats, suggesting a key role in enhanced GABA spillover. Baclofen did not alleviate mechanical allodynia. Diazepam failed to mitigate levcromakalim-induced migraine phenotype. Additionally, the resistant phenotype in GAERS was not affected by flumazenil. Extrasynaptic GABAA receptor agonists gaboxadol and muscimol inhibited periorbital allodynia in Wistar rats. Conclusion: Our study introduced a rat strain resistant to migraine-provoking agents and signified a critical involvement of extrasynaptic δGABAergic receptors. Extrasynaptic δ GABAA receptors, by mediating constant background inhibition on the excitability of neurons, stand as a novel drug target with a therapeutic potential in migraine. [ABSTRACT FROM AUTHOR]

Remimazolam's ultrashort-acting properties, including reduced injection discomfort, minimal impact on respiratory and cardiovascular functions and rapid metabolism, have garnered significant attention in the field of anesthesia. However, despite its widespread acclaim, we encountered an unusual case in which a patient without hepatic or renal impairment experienced unexpected delays in regaining consciousness following a single intravenous induction dose of remimazolam. The patient, a 63-yearold undergoing laparoscopic cholecystectomy for gallbladder stones, had preoperative tests revealing atrial fibrillation and a reduced ejection fraction observed in an echocardiogram. Anesthesia induction included the administration of remimazolam (0.3 mg/kg), sufentanil and rocuronium. The surgery proceeded uneventfully and was maintained with desflurane and sufentanil. However, after the surgery, the patient experienced delayed emergence from anesthesia. Opioid overdose was ruled out, and we suspected a metabolic delay associated with remimazolam. In response to this suspicion, we administered flumazenil, which promptly restored consciousness and normal breathing. Subsequent post-anesthetic observation revealed no complications, and the patient was discharged two days after surgery. This case highlights the significant delayed emergence phenomenon linked to remimazolam, even when administered as a bolus. Instances of delayed emergence following remimazolam administration underscore the complexities in anesthesia responses, emphasizing the importance of vigilant clinical monitoring and the need for ongoing research in this area. [ABSTRACT FROM AUTHOR]

Background: General anesthesia is often necessary for dental treatment of outpatients with mental disabilities. Rapid recovery and effective management of postoperative nausea and vomiting (PONV) are critical for outpatients. This study aimed to investigate the effect of transitioning from propofol to remimazolam with flumazenil reversal administered toward the end of surgery during propofol-based total intravenous anesthesia (TIVA) on recovery. Methods: Adults with mental disabilities scheduled to undergo dental treatment were randomly assigned to receive either propofol-based TIVA (Group P) or propofol-remimazolam-based TIVA with flumazenil reversal (Group PR). Propofol was replaced with remimazolam 1 h before the end of surgery in Group PR; moreover, 0.5 mg of flumazenil was administered after the neuromuscular blockade reversal agent. The primary outcome was the duration of stay in the post-anesthesia care unit (PACU). The secondary outcomes included time to eye-opening, time to extubation, occurrence of PONV, and quality of recovery. Results: Fifty-four patients were included in this study. The duration of stay in the PACU in Group PR was significantly shorter than that in Group P (mean difference, 8.7 min; confidence interval [95% CI], 3.3–14.2; P = 0.002). Group PR exhibited a shorter time to eye opening (mean difference, 5.4 min; 95% CI, 3.3–8.1; P < 0.001) and time to extubation (mean difference, 5.5 min; 95% CI, 3.6–7.9; P < 0.001) than Group P. Neither group required the administration of rescue analgesics, and the incidence of PONV was not reported. Conclusions: Transitioning from propofol to remimazolam 1 h before the end of surgery followed by flumazenil reversal reduced the duration of stay in the PACU and the time to eye opening and extubation without affecting the incidence of PONV and quality of recovery. Trial registration number: Clinical Research Information Service (KCT0007794), Clinical trial first registration date: 12/10/2022. [ABSTRACT FROM AUTHOR]

Anaesthesia induced with remimazolam and a fentanyl-series opioid can be reversed with flumazenil and naloxone. Concomitant paralysis with rocuronium can facilitate tracheal intubation whilst being reversible with sugammadex. Together, this combination might offer full reversibility of a 'routine' or a 'rapid-sequence' induction anaesthesia. Whether this is useful, or even safe, requires careful evaluation. [ABSTRACT FROM AUTHOR]

Muhammed Halit Satici,1 Nuray Altay2 1University of Health Sciences, Konya City Hospital Department of Anesthesiology and Reanimation, Konya, Turkey; 2Harran University, Faculty of Medicine, Department of Anesthesiology and Reanimation, &Scedil;anl&inodot;urfa, TurkeyCorrespondence: Muhammed Halit Satici, University of Health Sciences, Konya City Hospital, Department of Anesthesiology and Reanimation, Akabemahallesi, Adana çevreyolu, Cad. No: 135/1, Karatay, Konya, 42020, Turkey, Tel +905455636333, Email halit_satici@hotmail.com

A continuous infusion of flumazenil may be needed to mitigate prolonged sedation from benzodiazepines. Some benzodiazepines have extended durations of action. We describe a cirrhotic patient who was on an infusion of flumazenil for 37 days due to prolonged sedation from chlordiazepoxide. An 80-year-old man with alcohol use disorder and cirrhosis presented to the emergency department for abdominal distention and was admitted for management of ascites. On hospital day (HD) 2, he developed alcohol withdrawal, for which he received 350 mg of chlordiazepoxide over 48 h. Without receiving further sedatives, the patient remained deeply sedated. A bolus dose of flumazenil on HD 18 improved his mental status, allowing him to follow commands. A flumazenil infusion was started on HD 18. Serum chlordiazepoxide and nordiazepam concentrations were 230 ng/mL and 265 ng/mL, respectively, on hospital day 21, despite no additional doses since HD 4. The infusion was stopped 37 days after initiation (HD 55) and the patient was discharged on HD 76 to subacute rehabilitation. Patients with cirrhosis may develop prolonged sedation from chlordiazepoxide. This patient had detectable metabolites of chlordiazepoxide weeks after his last dose, which was associated with prolonged sedation managed with flumazenil infusion.

Hypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of "vascular" GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ2 and α1-5 subunit proteins. To confirm the role of "vascular" GABAA receptors, we investigated the vascular effects of standard benzodiazepines, midazolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5β3γ2 over other αxβ3γ2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazolam, both of which at 100 µmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators. [ABSTRACT FROM AUTHOR]

Objective To prepare flumazenil sublingual tablets and study its bioavailability. Methods Flumazenil sublingual tablets were prepared by compressing flumazenil inclusion compound with hydroxypropyl-β-cyclodextrin as the inclusion material. In a double-cycle crossover trial, twelve beagle dogs were randomly divided into two groups, one group receiving flumazenil sublingual tablets and the other receiving flumazenil injections. LC-MS method was developed and validated to determine flumazenil plasma concentration. The pharmacokinetic parameters and bioavailability were calculated using WinNonlin pharmacokinetic software. Results In the pharmacokinetic study, AUClast of flumazenil injection and sublingual tablet was (8.41±2.15) and (8.86±2.83) h·ng·ml−1, respectively; Cmax was (10.96±2.62) and (6.36±2.14) ng/ml, respectively; tmax was (0.18± 0.05) and (0.58±0.24) h, respectively. The bioavailability of flumazenil sublingual tablet was 52.68%. Conclusion Clathrates were used to prepare flumazenil sublingual tablets to achieve safe and efficient delivery. LC-MS method was established for the determination of flumazenil plasma concentration, and the advantages were simple, accurate and sensitive. [ABSTRACT FROM AUTHOR]

Objective To evaluate the effect of remimazolam combined with desflurane and flumazenil antagonism for anesthesia during ophthalmic day surgery. Methods This is a prospective randomized controlled trial. A total of 64 patients undergoing elective general anesthesia with laryngeal mask during ophthalmic day surgery were selected and randomly assigned to propofol group (n = 32) and remimazolam group (n = 32). The propofol group was given propofol anesthesia induction and propofol combined with diflurane anesthesia maintenance ; the remazolam group was given remazolam anesthesia induction and remazolam combined with diflurane anesthesia maintenance, and flumazenil antagonism was given intravenously at the end of the operation. Continuous intravenous infusion of remifentanil was administered during surgery in both groups. The primary outcome was emergence time. The secondary outcome included changes in intraoperative hemodynamic parameters, extubation time, time to leaving the operating room, duration of postoperative recovery room (PACU) stay, and the occurrence of other perioperative adverse reactions. Results Emergence time, extubation time, and time to leaving the operating room in remimazolam group were significantly shorter than those in group propofol (P < 0.05) [ (4.11 ± 1.17) vs. (8.64 ± 2.77)min, (4.61 ± 1.11) vs. (9.90 ± 2.81)min and (6.60 ± 2.01) vs. (11.74 ± 3.11)min, respectively]. The incidences of intraoperative hypotension and bradycardia in the remimazolam group were significantly lower than that in the propofol group (P < 0.05) ; There was no statistically difference in the duration of PACU stay and the incidence of postoperative complications between the two groups (P > 0.05). Conclusion Remimazolam combined with desflurane general anesthesia and flumazenil antagonism for anesthesia management in ophthalmic day surgery could significantly shorten he time of emergence and extubation, help to maintain hemodynamic stability with fewer adverse reactions, and improve the safety of ophthalmic daytime surgery, which is worthy of clinical promotion and application. [ABSTRACT FROM AUTHOR]

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Peganum harmala L. and Lavandula angustifolia are two traditional herbs with probable antiseizure effects. This study evaluated the effects of these two herbal extracts on pentylenetetrazol- (PTZ-) induced seizures in mice. We prepared hydroalcoholic extracts using P. harmala seeds and the aerial parts of L. angustifolia and then randomly divided 190 mice into 19 groups. Normal saline (10 mg/kg), diazepam (2 mg/kg), P. harmala (2.5, 5, 10, 15, 30, 45, and 60 mg/kg), and L. angustifolia (200, 400, 600, and 800 mg/kg) were intraperitoneally (IP) administrated 30 min before an IP administration of PTZ (90 mg/kg). Animals were observed for behavioral changes for one hour. In addition, the effects of flumazenil and naloxone on the antiseizure activity of P. harmala and L. angustifolia were assessed. P. harmala showed antiseizure activity at the dose of 10 mg/kg; it prolonged the seizure latency and decreased the seizure duration. The mortality protection rate was 90% for this herbal extract. L. angustifolia (600 mg/kg) prolonged the seizure latency and decreased both seizure duration and mortality. Neither flumazenil nor naloxone significantly reversed the antiseizure activities of P. harmala and L. angustifolia. In mice, the hydroalcoholic extracts of P. harmala and L. angustifolia showed antiseizure activity against PTZ-induced seizures. We could not delineate the exact antiseizure mechanisms of these extracts in the current study. [ABSTRACT FROM AUTHOR]

(1) Purpose: to systematically evaluate the recovery following sedation and anesthesia with remimazolam combined with flumazenil in comparison to propofol. (2) Methods: Electronic databases, including PubMed, Embase, Web of Science, and the Cochrane Library, were systematically searched from their inception up to 22 October 2023. Included in this analysis were randomized controlled trials (RCT) that compared remimazolam–flumazenil with propofol for the recovery from sedation and anesthesia in adults. The risk of bias was assessed using the Cochrane risk of bias tool. Pooled risk ratios (RR) or mean differences (MD) along with their corresponding 95% confidence intervals (CI) were calculated using either fixed-effects or random-effects models, and the results were visualized in forest plots. (3) Results: Nine RCTs involving 745 patients who underwent general anesthesia in three different countries were included. Compared to propofol, the remimazolam–flumazenil combination shortened the emergence time (MD = −4.34 min, 95% CI = [−6.88, −1.81], p = 0.0008, low certainty), extubation time (MD = −4.26 min, 95% CI = [−6.81, −1.7], p = 0.0011, low certainty), and the post-anesthesia care unit (PACU) stay (MD = −4.42 min, 95% CI = [−7.45, −1.38], p = 0.0044, low certainty), while reducing the incidence of respiratory depression (RR = 0.2, 95% CI = [0.04, 0.89], p = 0.03, high certainty) after general anesthesia. However, this combination was associated with a higher incidence of re-sedation (RR = 4.15, 95% CI = [1.31, 13.13], p = 0.01, moderate certainty). (4) Conclusions: Based on the existing evidence, the combination of remimazolam and flumazenil accelerates recovery from general anesthesia and lowers the risk of respiratory depression compared to propofol. However, it is important to consider the higher risk of re-sedation when using this combination in clinical practice. Due to limitations in the quality of the evidence, it is advisable to interpret the results of meta-analyses with caution. [ABSTRACT FROM AUTHOR]

Author(s): Kazuyoshi Hirota [sup.1] Author Affiliations: (1) grid.257016.7, 0000 0001 0673 6172, Department of Anesthesiology, Hirosaki University Graduate School of Medicine, , 036-8562, Hirosaki, Japan Remimazolam is a member of [...]

Abstract Background Compared to other intravenous anesthetics, availability of a specific antagonist flumazenil is a clear advantage of remimazolam. We report a patient who could be rapidly woken up when laryngoscopy and tracheal intubation were unexpectedly difficult. Case presentation A 62-year-old man was scheduled to have resection of a small gingival tumor. Preoperative airway examination was unremarkable except for an omega-shaped epiglottis. Anesthesia was induced with remifentanil/remimazolam infusion and rocuronium. A small omega-shaped edematous epiglottis precluded identification of glottis. Consciousness and spontaneous ventilation were rapidly restored after administration of flumazenil and sugammadex. Tracheostomy was done under local anesthesia while the patient breathed spontaneously. Conclusions Remimazolam can be a reasonable induction agent when there are concerns regarding airway management. Avoiding repeated airway manipulations is extremely important to prevent deterioration into a “cannot intubate, cannot ventilate (CICV)” emergency.

Author(s): Kenichi Masui [sup.1] Author Affiliations: (1) grid.268441.d, 0000 0001 1033 6139, Department of Anesthesiology, Yokohama City University School of Medicine, , Fukuura 3-9, Kanazawa-ku, 236-0004, Yokohama, Japan Introduction Remimazolam [...]

Abstract Background Remimazolam tosilate (RT) is a novel short-acting GABA (A) receptor agonist that has a rapid recovery from procedural sedation and can be fully reversed by flumazenil. To date, there have been relatively few articles comparing RT and propofol for general anesthesia. This study aimed to assess the efficacy and safety of RT with or without flumazenil compared with propofol in general anesthesia for day surgery. Methods 115 patients scheduled for day surgery were randomized into three groups: RT (n = 39), RT + flumazenil (n = 38) and propofol (n = 38). The primary endpoints were anesthesia induction time and time until fully alert. Anesthesia success rate, bispectral index (BIS) values, injection pain, opioid and vasopressor dosages, postoperative recovery profiles and perioperative inflammatory and cognitive changes were assessed. Any adverse events were recorded. Results Induction times were similar among the three groups (P = 0.437), but the median time until fully alert in patients treated with RT was longer than that of the propofol or RT + flumazenil groups (17.6 min vs. 12.3 min vs. 12.3 min, P 0.05). Smaller percentages of patients who received RT (26.3%) and RT + flumazenil (31.6%) developed hypotension during anesthesia maintenance compared with propofol (68.4%), and consequently less ephedrine (P

Abstract Background Previous studies have consistently reported a slower recovery of consciousness following remimazolam-based total intravenous anesthesia without flumazenil than with propofol. This study aimed to compare the reversal effect of flumazenil on the recovery of consciousness after remimazolam-based total intravenous anesthesia with the propofol recovery profile. Methods This prospective, single-blinded, randomized trial included 57 patients undergoing elective open thyroidectomy at a tertiary university hospital. Patients were randomly allocated to receive either remimazolam- or propofol-based total intravenous anesthesia (remimazolam group: 28 patients, propofol group: 29 patients). The primary outcome was the time from the end of general anesthesia to first eye opening (min). The secondary outcomes were the time from the end of the general anesthesia to extubation (min), initial modified Aldrete score measured at the post-anesthesia care unit, length of stay at the post-anesthesia care unit (min), occurrence of postoperative nausea and vomiting during the first 24 h postoperatively, and Korean version of Quality of Recovery-15 score at 24 h postoperatively. Results The remimazolam group showed significantly faster first eye opening time (2.3 [interquartile range, IQR: 1.8–3.3] min vs. 5.0 [IQR: 3.5–7.8] min, median difference:—2.7 [95% confidence interval, CI: -3.7 to -1.5] min, P

Background Remimazolam is a novel ultrashort-acting benzodiazepine that has recently become available for general anesthesia. However, the incidence of postoperative nausea and vomiting (PONV) associated with remimazolam remains unknown. In this propensity score-matched, retrospective, observational study, we compared the rates of PONV between remimazolam and propofol. Methods In this retrospective observational study, propensity score-matching was performed to minimize selection bias. Patients who received total intravenous anesthesia with remimazolam or propofol at the Hamamatsu University Hospital between August 2020 and July 2021 were enrolled in the study. Data on patient demographics, anesthetic agents, and PONV within the first 24 h were collected and analyzed. Results Of the 1,239 patients who met the study selection criteria, 585 received remimazolam and 684 received propofol. After propensity score matching, 333 matched pairs were further analyzed. Patient demographics and the anesthetic agents used were comparable between the matched cohorts. The incidence of PONV was significantly higher in the remimazolam group than in the propofol group (35% vs. 21%, P < 0.001). Conclusions The incidence of PONV is higher with remimazolam anesthesia than with propofol anesthesia. The findings of this study require confirmation in larger prospective randomized controlled trials.

Introduction: The fMRI BOLD response to emotional stimuli highlighting the role of the medial prefrontal cortex (MPFC) has been thoroughly investigated. Recently, the relationship between emotion processing and GABA levels has been studied using MPFC proton magnetic resonance spectroscopy (1H-MRS). However, the role of GABAA receptors in the MPFC during emotion processing remains unexplored. Methods: Using [11C]flumazenil PET, we investigated the relationship between the binding potential of GABAA receptors and emotion processing as measured using simultaneous fMRI BOLD. We hypothesized a correlation between the percent signal change in the BOLD signal and the binding potential of GABAA receptors in the MPFC. In a combined simultaneous fMRI and [11C]flumazenil-PET study, we analyzed the data from 15 healthy subjects using visual emotional stimuli. Our task comprised two types of emotional processing: passive viewing and appraisal. Following the administration of a bolus plus infusion protocol, PET and fMRI data were simultaneously acquired in a hybrid 3 T MR-BrainPET. Results: We found a differential correlation of BOLD percent signal change with [11C]flumazenil binding potential in the MPFC. Specifically, [11C]flumazenil binding potential in the ventromedial prefrontal cortex (vMPFC) correlated with passive viewing of emotionally valenced pictures. In contrast, the [11C]flumazenil binding potential and the BOLD signal induced by picture appraisal did show a correlation in the paracingulate gyrus. Conclusion: Our data deliver first evidence for a relationship between MPFC GABAA receptors and emotion processing in the same region. Moreover, we observed that GABAA receptors appear to play different roles in emotion processing in the vMPFC (passive viewing) and paracingulate gyrus (appraisal). [ABSTRACT FROM AUTHOR]

The short acting benzodiazepine remimazolam has been well characterised for use during procedural sedation. Onset of hypnotic effect is swifter than midazolam and recovery is faster with a period of antegrade amnesia. Haemodynamic changes associated with remimazolam sedation are modest and there is no pain on injection. General anaesthesia may be induced and maintained by infusion of remimazolam in combination with a suitable opioid. Hypotension is less frequent than when propofol is used. In addition, remimazolam may be a suitable alternative to propofol or etomidate for inducing anaesthesia in haemodynamically compromised patients prior to maintenance with a volatile agent. A small proportion of patients are slow to recover consciousness after total intravenous anaesthesia (TIVA) with remimazolam/opioid combinations. Preliminary experience suggests that flumazenil may be useful in this group however studies are required to define the appropriate dosage and timing for flumazenil administration. Future developments may include sedation and anaesthesia for infants and children as well as intensive care sedation for all age groups. These indications require demonstration in well designed clinical trials. [ABSTRACT FROM AUTHOR]

Background: Compared to other intravenous anesthetics, availability of a specific antagonist flumazenil is a clear advantage of remimazolam. We report a patient who could be rapidly woken up when laryngoscopy and tracheal intubation were unexpectedly difficult. Case presentation: A 62-year-old man was scheduled to have resection of a small gingival tumor. Preoperative airway examination was unremarkable except for an omega-shaped epiglottis. Anesthesia was induced with remifentanil/remimazolam infusion and rocuronium. A small omega-shaped edematous epiglottis precluded identification of glottis. Consciousness and spontaneous ventilation were rapidly restored after administration of flumazenil and sugammadex. Tracheostomy was done under local anesthesia while the patient breathed spontaneously. Conclusions: Remimazolam can be a reasonable induction agent when there are concerns regarding airway management. Avoiding repeated airway manipulations is extremely important to prevent deterioration into a "cannot intubate, cannot ventilate (CICV)" emergency. [ABSTRACT FROM AUTHOR]

Background: Epilepsy is a common neurological disorder. The available drugs for this disease only control convulsions in nearly 70% of patients, while bearing many side effects. In this study, a new series of phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid hybrids 8a-m was designed, synthesized, and evaluated as potent anticonvulsant agents. Methods: Phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid derivatives 8a-m were synthesized with well-known chemical reactions and anticonvulsant activity of them was determined by pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizures in mice. Phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid scaffold has the necessary pharmacophores to be a benzodiazepine (BZD) receptor agonist, thus, the most potent anticonvulsant compounds were assayed in vivo and in silico as BZD receptor agonist. Furthermore, in vivo neurotoxicity evaluation and in silico physicochemical, pharmacokinetic, and toxicity study on the most potent compounds were also performed. Results: Obtained results demonstrated that two compounds among the title new compounds have anticonvulsant activity in PTZ test while all of the new compounds are active in the MES test. The best anticonvulsant activities were obtained with nitro derivatives 8k and 8L. In vivo evaluation of flumazenil effect (a BZD receptor antagonist) on anticonvulsant activity of compound 8k confirmed that this compound is a BZD receptor agonist. The most potent compounds 8k and 8L interacted with the important residues of BZD-binding site of GABAA receptor. Furthermore, neurotoxicity of the latter compounds was lower than positive control diazepam. Conclusion: According to these results, our designed scaffold can be a valuable lead structure for further structural developments and assessments to obtain a new potent anticonvulsant agent. [ABSTRACT FROM AUTHOR]

Introduction: Medications which target benzodiazepine (BZD) binding sites of GABAA receptors (GABAARs) have been in widespread use since the nineteen-sixties. They carry labels as anxiolytics, hypnotics or antiepileptics. All benzodiazepines and several nonbenzodiazepine Z-drugs share high affinity binding sites on certain subtypes of GABAA receptors, from which they can be displaced by the clinically used antagonist flumazenil. Additional binding sites exist and overlap in part with sites used by some general anaesthetics and barbiturates. Despite substantial preclinical efforts, it remains unclear which receptor subtypes and ligand features mediate individual drug effects. There is a paucity of literature comparing clinically observed adverse effect liabilities across substances in methodologically coherent ways. Methods: In order to examine heterogeneity in clinical outcome, we screened the publicly available U.S. FDA adverse event reporting system (FAERS) database for reports of individual compounds and analyzed them for each sex individually with the use of disproportionality analysis. The complementary use of physico-chemical descriptors provides a molecular basis for the analysis of clinical observations of wanted and unwanted drug effects. Results and Discussion: We found a multifaceted FAERS picture, and suggest that more thorough clinical and pharmacoepidemiologic investigations of the heterogenous side effect profiles for benzodiazepines and Z-drugs are needed. This may lead to more differentiated safety profiles and prescription practice for particular compounds, which in turn could potentially ease side effect burden in everyday clinical practice considerably. From both preclinical literature and pharmacovigilance data, there is converging evidence that this very large class of psychoactive molecules displays a broad range of distinctive unwanted effect profiles - too broad to be explained by the four canonical, so-called "diazepam-sensitive high-affinity interaction sites". The substance-specific signatures of compound effects may partly be mediated by phenomena such as occupancy of additional binding sites, and/or synergistic interactions with endogenous substances like steroids and endocannabinoids. These in turn drive the wanted and unwanted effects and sex differences of individual compounds. [ABSTRACT FROM AUTHOR]

Purpose This study was performed to examine and compare the incidence of extubation recall in surgical patients who underwent remimazolam anesthesia with flumazenil antagonism during emergence and in those who underwent propofol anesthesia. Methods One hundred sixty-three patients who underwent surgery using general endotracheal or supraglottic airway anesthesia with propofol (n = 97) or remimazolam (n = 66) were retrospectively analyzed. Remimazolam was antagonized by flumazenil after discontinuation of remimazolam at the end of surgery. The endotracheal tube or supraglottic airway was removed after surgery was complete, and consciousness and adequate spontaneous breathing were confirmed. The incidence of extubation recall was compared between the remimazolam and propofol anesthesia groups using propensity score matching. Results Extubation recall was observed in 28 patients (17%). After propensity score matching, the incidence of extubation recall did not significantly differ between the remimazolam and propofol anesthesia groups (15.6% vs. 18.8%; p = 1.000). Conclusion The incidence of extubation recall after remimazolam anesthesia with flumazenil antagonism during emergence did not significantly differ from that after propofol anesthesia., Author(s): Tsunehisa Sato [sup.1], Soichiro Mimuro [sup.2], Tadayoshi Kurita [sup.2], Mayumi Kobayashi [sup.2], Matsuyuki Doi [sup.2], Takasumi Katoh [sup.2], Yoshiki Nakajima [sup.2] Author Affiliations: (1) Department of Anesthesiology, Suzukake Central [...]