Comparison of Manual Restraint With and Without Sedation on Outcomes for Wild Birds Undergoing Decontamination.

The decontamination process for plumage-contaminated wild birds, such as those affected by oil spills, is lengthy and involves manual restraint and manipulation of all body parts. Birds commonly react to this in ways that suggest they are extremely stressed (eg, struggling, vocalizing). We proposed to reduce stress during the wash process using sedation and hypothesized that the use of sedation would not negatively impact survival. Contaminated birds in need of washing were randomly selected to be either sedated (butorphanol 2 mg/kg IM + midazolam 1 mg/kg IM and flumazenil 0.1 mg/kg IM for reversal) or not sedated at 3 US rehabilitation centers over the course of 1 year. Response to sedation was rated on a scale of 0-4 with 0 as no effect to 4 as excessively sedate. Data such as cloacal temperatures at various time points, lengths of various portions of the wash process, preening behavior in the drying pen, and disposition were collected. No statistical differences were found between sedated and nonsedated birds for any of the data points collected, including survival. There was a significant association between birds with higher cloacal temperatures in the drying pen and with birds held longer in the drying pen with improved survival; however, these findings were unrelated to whether the birds were sedated. Our findings show that sedation with butorphanol 2 mg/ kg IM and midazolam 1 mg/kg IM reversed with flumazenil 0.1 mg/kg IM can be used during the wash process for wild birds without adverse effects. Careful attention must be given to heat support for all birds while drying to prevent hypothermia.

Protective effect of flumazenil infusion in severe acute benzodiazepine toxicity: a pilot randomized trial.

OBJECTIVE: We aimed to investigate the efficacy of flumazenil infusion in the maintenance of arousal and prevention of development of complications in severe benzodiazepine poisoning. MATERIALS AND METHOD: Sixty severely poisoned patients (intubated due to loss of consciousness) intoxicated by sole benzodiazepines referred to Loghman Hakim hospital between May 2018 and August 2019 were considered to be included in the current study. All were evaluated for possible contraindications of flumazenil administration. If there were no contraindications, we continued supportive care in one group and supportive care plus flumazenil infusion in the second group. Following response to the stat dose of flumazenil, complications, hospital stay, and outcome were compared between these two groups. RESULTS: A total of 60 benzodiazepine-poisoned patients aged between 16 and 84 years old (37 males and 23 females) were enrolled. There was no statistically significant difference between these two groups regarding the period of hospital stay. Need for intubation significantly decreased in the infusion group. None of the patients experienced seizure or dysrhythmia. One patient died in the control group which received only a stat dose of flumazenil. CONCLUSIONS: Administration of flumazenil is safe in benzodiazepine-poisoned patients with appropriate indications. Flumazenil infusion can significantly decrease the need for intubation and subsequent ICU admission. Even though flumazenil is an expensive antidote, its administration may decrease the need for ICU beds in the setting of acute poisoning.

Bolus infusion scheme for the adjustment of steady state [11C]Flumazenil levels in the grey matter and in the blood plasma for neuroreceptor imaging.

The use of hybrid PET/MR imaging facilitates the simultaneous investigation of challenge-related changes in ligand binding to neuroreceptors using PET, while concurrently measuring neuroactivation or blood flow with MRI. Having attained a steady state of the PET radiotracer using a bolus-infusion protocol, it is possible to observe alterations in ligand neuroreceptor binding through changes in distribution volumes. Here, we present an iterative procedure for establishing an administration scheme to obtain steady state [11C]flumazenil concentrations in grey matter in the human brain. In order to achieve a steady state in the shortest possible time, the bolus infusion ratio from a previous examination was adapted to fit the subsequent examination. 17 male volunteers were included in the study. Boli and infusions with different weightings were given to the subjects and were characterised by kbol values from 74 â€‹min down to 42 â€‹min. Metabolite analysis was used to ascertain the value of unmetabolised flumazenil in the plasma, and PET imaging was used to assess its binding in the grey matter. The flumazenil time-activity curves (TACs) in the brain were decomposed into activity contributions from pure grey and white matter and analysed for 12 â€‹vol of interest (VOIs). The curves highlighted a large variability in metabolic rates between the subjects, with kbol â€‹= â€‹54.3 â€‹min being a reliable value to provide flumazenil equilibrium conditions in the majority of the VOIs and cases. The distribution volume of flumazenil in all 12 VOIs was determined.

The role of hippocampal GABAA receptors on anxiolytic effects of Echium amoenum extract in a mice model of restraint stress.

Echium amoenum (EA), a popular medicinal plant in Persian medicine, has anxiolytic, antioxidant, sedative, and anti-inflammatory effects. This study examined whether GABA-ergic signaling is involved in the anxiolytic effects of EA in mice. Sixty BALB/c mice (25-30 g) were divided into six groups (n = 10) as follows: the (I) control group received 10 ml/kg normal saline (NS). In the stress groups, the animals underwent 14 consecutive days of restraint stress (RS), and received following treatments simultaneously; (II) RS + NS; (III) RS + Diaz (Diazepam); (IV) RS + EA; (V) RS + Flu (Flumazenil) + EA; (VI) RS + Flu + Diaz. Behavioral tests including the open field test (OFT) and elevated plus maze (EPM) were performed to evaluate anxiety-like behaviors and the effects of the regimens. The plasma level of corticosterone and the hippocampal protein expressions of IL-1ß, TNF-α, CREB, and BDNF, as well as p-GABAA/GABAA ratio, were also assessed. The findings revealed that chronic administration of EA alone produced anxiolytic effects in both behavioral tests, while diazepam alone or in combination with Flu failed to decrease the anxiety-like behaviors. Furthermore, the p-GABAA/GABAA and p-CREB/CREB ratios, and protein levels of BDNF were significantly increased in the EA-received group. On the other hand, plasma corticosterone levels and the hippocampal IL-1ß and TNF-α levels were significantly decreased by EA. However, pre-treatment with GABAA receptors (GABAA Rs) antagonist, Flu, reversed the anxiolytic and molecular effects of EA in the RS-subjected animals. Our findings confirmed that alternation of GABAAR is involved in the effects of EA against RS-induced anxiety-like behaviors, HPA axis activation, and neuroinflammation.

COMPARISON OF SUBCUTANEOUS ADMINISTRATION OF ALFAXALONE-MIDAZOLAM-DEXMEDETOMIDINE WITH KETAMINE-MIDAZOLAM-DEXMEDETOMIDINE FOR CHEMICAL RESTRAINT IN JUVENILE BLUE POISON DART FROGS (DENDROBATES TINCTORIUS AZUREUS).

Blue poison dart frogs (Dendrobates tinctorius azureus) are commonly maintained in zoological institutions and are becoming popular in the pet trade industry. Sedation or light anesthesia is required for safe and effective handling of this species. In this study, the sedative effects of subcutaneously administered alfaxalone-midazolam-dexmedetomidine (AMD) (20, 40, 5 mg/kg, respectively) and ketamine-midazolam-dexmedetomidine (KMD) (100, 40, 5 mg/kg, respectively) were compared in a prospective, randomized, blinded, crossover study in juvenile blue poison dart frogs (n = 10). Both protocols were partially reversed 45 min after administration of either protocol with subcutaneously administered flumazenil (0.05 mg/kg) and atipamezole (50 mg/kg). Heart rate, pulmonic respiratory rate, various reflexes, and behavioral parameters were monitored after drug administration. Both protocols resulted in rapid loss of righting reflex [median (range): AMD, 5 min (5-5 min); KMD, 5 min (5-10 min)]. Time to complete recovery was similar with both protocols (mean ± SD: AMD, 97.5 ± 11.4 min; KMD, 96.5 ± 25.4 min). The AMD protocol resulted in pulmonic respiratory depression, whereas no significant difference in heart rate was found between the two protocols. All frogs were observed eating within 24 hr of chemical restraint. Gastric prolapses occurred in four frogs (AMD 3, KMD 1) that were easily reduced with a cotton-tip application. No other adverse reactions were observed. The results of this study provide two different subcutaneous chemical restraint protocols in juvenile blue poison dart frogs.

EVALUATION OF THE EFFECTS OF MIDAZOLAM AND FLUMAZENIL IN THE BALL PYTHON (PYTHON REGIUS).

The study objective was to evaluate the sedative, muscle relaxant, and cardiorespiratory effects of midazolam and flumazenil in the ball python (Python regius). Ten healthy adult female ball pythons were used in a randomized and blinded crossover trial evaluating the effects of two dosages (1 and 2 mg/kg intramuscular [i.m.] in the cranial third of the body). In a subsequent open trial, nine ball pythons received 1 mg/kg i.m. of midazolam followed by 0.08 mg/kg i.m. of flumazenil 60 min later. Heart rate, respiratory rate, temperature, and the level of sedation and muscle relaxation (using a semiobjective scoring system) were evaluated. There were no significant differences between midazolam dosages for any of the parameters evaluated. Sedation scores were significantly increased compared with baseline from 15 min (1 mg/kg) and 10 min (2 mg/kg) postinjection up until 56 hr (1 mg/kg) and 72 hr (2 mg/kg) postinjection. Peak effect was reached 60 min postinjection, with 60% of snakes (6/10) being unable to right themselves. One snake developed paradoxical excitation with the 2 mg/kg dosage. Heart rates were significantly lower than baseline from 30 min to 128 hr postinjection with both midazolam dosages. Respiratory rates were significantly lower than baseline at four time points, with the highest dosage only: 15, 45, 60 min, and 8 hr postinjection. Flumazenil resulted in reversal of sedation and muscle relaxation in all snakes within 10 min of administration. However, resedation was evident in all snakes 3 hr after reversal. Midazolam administered at 1 and 2 mg/kg i.m. provides a moderate to profound, although prolonged, sedation and muscle relaxation in ball pythons. Flumazenil reverses the effects of midazolam in ball pythons, but its duration of action at the evaluated dosage is much shorter than midazolam, leading to resedation.

Review of Intranasally Administered Medications for Use in the Emergency Department.

BACKGROUND: Intranasal (IN) medication delivery is a viable alternative to other routes of administration, including intravenous (IV) and intramuscular (IM) administration. The IN route bypasses the risk of needle-stick injuries and alleviates the emotional trauma that may arise from the insertion of an IV catheter. OBJECTIVE: This review aims to evaluate published literature on medications administered via the IN route that are applicable to practice in emergency medicine. DISCUSSION: The nasal mucosa is highly vascularized, and the olfactory tissues provide a direct conduit to the central nervous system, bypass first-pass metabolism, and lead to an onset of action similar to IV drug administration. This route of administration has also been shown to decrease delays in drug administration, which can have a profound impact in a variety of emergent scenarios, such as seizures, acutely agitated or combative patients, and trauma management. IN administration of midazolam, lorazepam, flumazenil, dexmedetomidine, ketamine, fentanyl, hydromorphone, butorphanol, naloxone, insulin, and haloperidol has been shown to be a safe, effective alternative to IM or IV administration. As the use of IN medications becomes a more common route of administration in the emergency department setting, and in prehospital and outpatient settings, it is increasingly important for providers to become more familiar with the nuances of this novel route of medication delivery. CONCLUSIONS: IN administration of the reviewed medications has been shown to be a safe and effective alternative to IM or IV administration. Use of IN is becoming more commonplace in the emergency department setting and in prehospital settings.

Effects of γ-Aminobutyric Acid Type A Receptor Modulation by Flumazenil on Emergence from General Anesthesia.

BACKGROUND: Transitions into conscious states are partially mediated by inactivation of sleep networks and activation of arousal networks. Pharmacologic hastening of emergence from general anesthesia has largely focused on activating subcortical monoaminergic networks, with little attention on antagonizing the γ-aminobutyric acid type A receptor (GABAAR). As the GABAAR mediates the clinical effects of many common general anesthetics, the authors hypothesized that negative GABAAR modulators would hasten emergence, possibly via cortical networks involved in sleep. METHODS: The authors investigated the capacity of the benzodiazepine rescue agent, flumazenil, which had been recently shown to promote wakefulness in hypersomnia patients, to alter emergence. Using an in vivo rodent model and an in vitro GABAAR heterologous expression system, they measured flumazenil's effects on behavioral, neurophysiologic, and electrophysiologic correlates of emergence from isoflurane anesthesia. RESULTS: Animals administered intravenous flumazenil (0.4 mg/kg, n = 8) exhibited hastened emergence compared to saline-treated animals (n = 8) at cessation of isoflurane anesthesia. Wake-like electroencephalographic patterns occurred sooner and exhibited more high-frequency electroencephalography power after flumazenil administration (median latency ± median absolute deviation: 290 ± 34 s) compared to saline administration (473 ± 186 s; P = 0.042). Moreover, in flumazenil-treated animals, there was a decreased impact on postanesthesia sleep. In vitro experiments in human embryonic kidney-293T cells demonstrated that flumazenil inhibited isoflurane-mediated GABA current enhancement (n = 34 cells, 88.7 ± 2.42% potentiation at 3 µM). Moreover, flumazenil exhibited weak agonist activity on the GABAAR (n = 10 cells, 10.3 ± 3.96% peak GABA EC20 current at 1 µM). CONCLUSIONS: Flumazenil can modulate emergence from isoflurane anesthesia. The authors highlight the complex role GABAARs play in mediating consciousness and provide mechanistic links between emergence from anesthesia and arousal.

Risk Factors and Outcomes of Reversal Agent Use in Moderate Sedation During Endoscopy and Colonoscopy.

BACKGROUND: Moderate sedation has been standard for noninvasive gastrointestinal procedures for decades yet there are limited data on reversal agent use and outcomes associated with need for reversal of sedation. AIM: To determine prevalence and clinical significance of reversal agent use during endoscopies and colonoscopies. METHODS: Individuals with adverse events requiring naloxone and/or flumazenil during endoscopy or colonoscopy from 2008 to 2013 were identified. A control group was obtained by random selection of patients matched by procedure type and date. Prevalence of reversal agent use and statistical comparison of patient demographics and risk factors against controls were determined. RESULTS: Prevalence of reversal agent use was 0.03% [95% confidence interval (CI), 0.02-0.04]. Events triggering reversal use were oxygen desaturation (64.4%), respiration changes (24.4%), hypotension (8.9%), and bradycardia (6.7%). Two patients required escalation of care and the majority of patients were stabilized and discharged home. Compared with the control group, the reversal group was older (61±1.8 vs. 55±1.6, P=0.01), mostly female (82% vs. 50%, P<0.01), and had lower body mass index (24±0.8 vs. 27±0.7, P=0.03) but received similar dosages of sedation. When adjusted for age, race, sex, and body mass index, the odds of reversal agent patients having a higher ASA score than controls was 4.7 (95% CI, 1.7-13.1), and the odds of having a higher Mallampati score than controls was 5.0 (95% CI, 2.1-11.7) with P<0.01. CONCLUSIONS: Prevalence of reversal agent use during moderate sedation is low and outcomes are generally good. Several clinically relevant risk factors for reversal agent use were found suggesting that certain groups may benefit from closer monitoring.

Inhalation of 50% Oxygen Does Not Impair Respiratory Depression During Midazolam Sedation.

PURPOSE: To investigate how inhalation of 50% oxygen during intravenous midazolam sedation affects respiratory variables and thus the availability of oxygen. MATERIALS AND METHODS: Study subjects were 21 healthy adult volunteers (American Society of Anesthesiologists physical status I). They were allocated to undergo midazolam sedation during high-concentration oxygen inhalation (group H) or during normal air inhalation (group N) in a single-blinded randomized crossover design, with an interval of at least 3 days between the 2 sedation sessions. In each experiment, midazolam 0.05 mg/kg was administered, after which the following variables were measured for 40 minutes: oxygen saturation by pulse oximetry (SpO2), end-tidal carbon dioxide partial pressure (ETCO2), respiration rate (RR), tidal volume (VT), and minute volume (MV). Subsequently, flumazenil 0.5 mg was administered, and the same variables were measured for 10 minutes. RESULTS: SpO2 decreased after midazolam administration in the 2 groups. SpO2 in group H was higher than that in group N at all time points. RR increased and VT decreased after midazolam administration in the 2 groups; however, in contrast to SpO2, the levels of these parameters did not meaningfully differ between groups at any time point. MV remained unchanged in the 2 groups. ETCO2 decreased similarly after midazolam administration in the 2 groups. CONCLUSION: Inhalation of 50% oxygen during midazolam sedation did not enhance respiratory depression by midazolam. This suggests that high-concentration oxygen inhalation during midazolam sedation could prevent hypoxia.

Benzodiazepines: Sedation and Agitation.

Dental anxiety is common and frequently poses a barrier to necessary dental treatment. The increasing availability of conscious sedation in dental practice has made treatment much more accessible for anxious patients. At present, benzodiazepines are the most commonly used drugs in sedation practice and provide a pleasant experience for most, but not all, patients. An understanding of the mechanism of action of benzodiazepines should inform our practice and deepen our understanding of why and how sedation may fail. CPD/CLINICAL RELEVANCE: As an increasing number of dentists provide sedation for their patients an update on benzodiazepines is timely.

Conscious Sedation Using Midazolam and Sequential Flumazenil in Cirrhotic Patients for Prophylactic Endoscopic Variceal Ligation.

BACKGROUND/AIMS: This study investigated the safety of endoscopic variceal ligation (EVL) under conscious sedation with midazolam and sequential flumazenil after procedure in these patients. METHODS: A total of 279 patients who underwent secondary prophylactic EVL at our institution between April 2012 and June 2014, were enrolled. Conscious sedation was achieved using intravenous midazolam, and flumazenil was routinely used as an antidote immediately after EVL. Patients with sleep (n = 165) and non-sleep (n = 55) endoscopy were matched using propensity score analysis (3:1). Frequencies of overt hepatic encephalopathy (HEP) and patient' satisfactions with EVL were compared between the 2 groups. RESULTS: Of the 279 patients, 155 (55.6%) were of Child-Turcotte-Pugh (CTP) class, B or C, and 224 (80.3%) patients underwent sleep endoscopy. After propensity score analysis, overt HEP was observed in 1 (0.4%) of the 165 patients in the sedated group, but not found in any in the non-sedated group. Patient' satisfaction with EVL was better in the sedated group (p < 0.001). Twenty-nine (65.9%) of the 44 patients with CTP class C underwent sleep endoscopy, and only one (3.4%) experienced overt HEP. CONCLUSIONS: Prophylactic EVL under conscious sedation using midazolam and flumazenil is probably safe in cirrhotic patients without experience of HEP, even in those of CTP class C.

Prescription Sedative Misuse and Abuse.

Sedatives are widely prescribed for anxiety or insomnia and include benzodiazepines, selective benzodiazepine receptor subtype agonists (z-drugs), and barbiturates. These sedatives are controlled substances due to their potential for misuse and abuse. Misuse is often self-medication (chemical coping) of psychological symptoms in ways unauthorized by the prescriber, usually as dose escalation leading to requests for early refills. Sedatives are abused for euphoric effects, which may have dangerous consequences. Some sedative overdoses can be treated with flumazenil, a reversal agent, along with supportive care. Sedative withdrawal syndrome is treated by tapering the sedative and may require hospitalization. Long-term treatment of sedative addiction requires counseling, often with the help of an addiction-treatment professional.

Benzodiazepine dependence and its treatment with low dose flumazenil.

Globally benzodiazepines remain one of the most prescribed medication groups, especially in the primary care setting. With such high levels of prescribing it is not surprising that benzodiazepine dependence is common, cutting across all socioeconomic levels. Despite recognition of the potential for the development of iatrogenic dependence and the lack of any effective treatment, benzodiazepines continue to be widely prescribed in general practice. Conventional dependence management, benzodiazepine tapering, is commonly a protracted process over several weeks or months. It is often associated with significant withdrawal symptoms and craving leading to patient drop out and return to use. Accordingly, there is a worldwide need to find effective pharmacotherapeutic interventions for benzodiazepine dependence. One drug of increasing interest is the GABAA benzodiazepine receptor antagonist/partial agonist, flumazenil. Multiple bolus intravenous infusions of low dose flumazenil used either with or without benzodiazepine tapering can reduce withdrawal sequelae, and/or longer term symptoms in the months following withdrawal. Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for 4 days significantly reduces acute benzodiazepine withdrawal sequelae. The subcutaneous infusion was shown to be tissue compatible so the development of a longer acting (i.e. several weeks) depot flumazenil formulation has been explored. This could be capable of managing both acute and longer term benzodiazepine withdrawal sequelae. Preliminary in vitro water bath and in vivo biocompatibility data in sheep show that such an implant is feasible and so is likely to be used in clinical trials in the near future.

Significant and safe shortening of the recovery time after flumazenil-reversed midazolam sedation.

BACKGROUND: Endoscopy under midazolam sedation requires a 2-h recovery facility. AIM: To study the potential of shortening patients' stay without jeopardizing patients' safety by the use of the benzodiazepine-antagonist flumazenil in the everyday practice and to investigate the feasibility of a study comparing midazolam with recovery with midazolam-flumazenil and immediate discharge. METHODS: Consecutive ambulatory patients referred for endoscopy under midazolam sedation with ASA I or II, escorted by a person, were eligible. Flumazenil was given on arrival in the recovery room. Patients were discharged when adequate Aldrete scores and physical mobility were present. The next day, they were contacted by telephone. RESULTS: A total of 1,506 patients participated. They received 5 mg midazolam, while 887 patients also received 50 mcg fentanyl. The median dose of flumazenil was 0.2 mg. Oxygen desaturation (sO2 <92%) occurred in 15% during the procedure without an effect on recovery and discharge times. Patients left the department 65 min after the last midazolam administration. The majority (82.7%) were fully alert during their journey home. At home, 2.7% went to bed, 45.2% took a nap, and 40% undertook activities. Almost every patient (98.8%) liked the shortened recovery time. Three patients had an incident (fainting, fall, and near-fall) without consequences. Based on this low incidence, a non-inferiority comparison of midazolam-flumazenil with midazolam-recovery would require a total of 32,650 patients. CONCLUSIONS: Administration of flumazenil resulted in a safe shortening of the recovery period and offers the possibility for substantial savings in time, space, and nurse resources. A non-inferiority comparison will not be practicable.

Comparison of Remimazolam Tosilate and Propofol Sedation on the Early Postoperative Quality of Recovery in Patients Undergoing Day Surgery: A Prospective Randomized Controlled Trial.

Purpose: 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.

Remimazolam-flumazenil provides fast recovery from general anesthesia compared to propofol during radiofrequency catheter ablation of atrial fibrillation.

The optimal anesthetic agent for radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) and its impact on the recovery profiles remain uncertain. We compared the recovery and hemodynamic parameters between the remimazolam-flumazenil and propofol groups during RFCA. Patients were randomized into the remimazolam-flumazenil and propofol groups. The primary outcome measure was the time to eye opening following the discontinuation of anesthetic agents. Secondary outcomes included time to extubation, time to discharge from the operating room, intraprocedural hemodynamic variables and postoperative quality outcomes. Fifty-three patients were included in the final analysis (n = 26 in the remimazolam-flumazenil and n = 27 in the propofol group). The time to eye opening was significantly shorter in the remimazolam-flumazenil group compared to the propofol group (median [interquartile range]: 174 [157-216] vs. 353 [230-483] s, P < 0.001). The mean blood pressure and bispectral index were significantly higher in the remimazolam-flumazenil group compared to the propofol group (mean difference [95% CI], 7.2 [1.7-12.7] mmHg and 6 [3-8]; P = 0.011 and < 0.001, respectively), which were within target ranges in both groups. Other secondary outcomes were comparable between the groups. Consequently, remimazolam emerges as a promising anesthetic agent, characterized by rapid recovery and stable hemodynamics, during RFCA of AF.Trial registration: NCT05397886.

[Flumazenil].

Flumazenil, an imidazobenzodiazepine derivative, has been generally used as an antagonist which antagonizes the hypnotic and sedative effects of benzodiazepines at gamma-amino butyric acid receptors. The anesthetic effects induced by benzodiazepine could be reversed effectively and safely by flumazenil alone, and some have recommended diagnostic usage in intensive care unit and emergency unit as well, for suspected benzodiazepine intoxication. Seizures might follow the use of flumazenil. Benzodiazepine overdose patients who have co-ingested tricyclic and tetracyclic antidepressants are especially at risk for this complication. Therefore, flumazenil could be considered in cases in which quick recovery is required and should be administered intravenously in small, incremental doses.

Focal nonconvulsive seizures during detoxification for benzodiazepine abuse.

Chronic benzodiazepine (BDZ) abuse is currently treated with detoxification using a low-dose flumazenil infusion, a relatively recently developed and promising procedure. Given the possibility reported in the literature of the occurrence of generalized seizures during therapeutic BDZ detoxification, we usually administer preventive antiepileptic drug (AED) therapy. We describe two patients with no previous history of seizures or evidence of intracerebral lesions who, during detoxification for benzodiazepine abuse, developed repetitive focal nonconvulsive seizures instead of generalized seizures, even with appropriate doses of preventive AED therapy. There are no previous reported cases of focal nonconvulsive seizures occurring during this procedure or, more generally, during abrupt BDZ discontinuation. The cases we describe suggest that during detoxification for BDZ abuse, not only generalized, but also focal nonconvulsive seizures may occur. In this context, the focal seizures probably result from a diffuse decrease in the seizure threshold (caused by a generalized excitatory rebound), which may trigger focal seizures arising from cortical regions with higher intrinsic epileptogenicity. Detoxification for benzodiazepine abuse, even if performed with adequate-dosage AED treatment, may not be as safe a procedure as previously considered, because not only convulsive, but also nonconvulsive seizures may occur and go unnoticed. It is therefore strongly advisable to perform this detoxification under close medical supervision and to maintain a low threshold for EEG monitoring in the event of sudden onset of behavioral changes.