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Background: Flumazenil is a competitive benzodiazepine (BZD) antagonist most used for treating delirium in BZD overdoses. Since its introduction, many have expressed concerns about its safety secondary to the risk of inducing BZD withdrawal and refractory seizures., Study Question: What is the incidence of adverse drug events after the administration of flumazenil in patients with suspected iatrogenic BZD delirium?, Study Design: This is a retrospective cross-sectional study of patients from a single center from 2010 to 2013. Patients experiencing delirium after receiving BZDs in the hospital were included if they had a bedside toxicology consult and were administered flumazenil. Patients were excluded if they were given BZDs for ethanol withdrawal or if they did not have mental status documentation before and after flumazenil administration. Descriptive statistics were calculated., Measures and Outcomes: The primary outcome was the incidence of adverse drug events after flumazenil administration. The secondary outcome was the efficacy of flumazenil determined by the patient's mental status., Results: A total of 501 patient records were reviewed, and 206 patients were included in the final analysis. Of those patients, 172 (83.5%) experienced an objective improvement in their mental status within 1 hour after flumazenil administration. A total of 5 patients experienced adverse events (2.4%), 95% confidence interval (0.78, 5.54). Of these, 3 patients experienced minor agitation or restlessness without pharmacologic intervention. Two patients experienced moderate agitation or restlessness that resolved with haloperidol or physostigmine administration. No patients had a reported seizure, 95% confidence interval (0.0, 1.77)., Conclusions: Flumazenil seems to be a safe and effective intervention for the reversal of delirium secondary to iatrogenic BZD administration., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Study Objective: The emergence profiles in patients undergoing total intravenous anesthesia with either propofol or remimazolam with flumazenil reversal were compared., Design: A prospective, double-blind, randomized trial., Setting: An operating room and a post-anesthesia care unit (PACU)., Patients: Adult patients (n = 100) having American Society of Anesthesiologists (ASA) physical status of I-III undergoing general anesthesia were enrolled and randomly assigned to the propofol or the remimazolam group., Interventions: The propofol group received target-controlled infusion of propofol, and the remimazolam group received continuous infusion of remimazolam. Continuous infusion of remifentanil was used in both groups. For emergence, flumazenil was used in increments of 0.2 mg in the remimazolam group., Measurements: The primary outcome was the time required for the patient to obey verbal commands. The secondary outcomes included the time to bispectral index (BIS) over 80, the time to laryngeal mask airway (LMA) removal, the Richmond Agitation-Sedation Scale (RASS) scores in the PACU, and adverse events throughout the study period., Main Results: The time taken to obey verbal commands was significantly longer in the propofol group than the remimazolam group (14 [9, 19]) vs. 5 [3, 7]) minutes, P < 0.001; median difference -9, 95% confidence interval -11 to -6). The times to BIS over 80 and to LMA removal were also significantly longer in the propofol group. In addition, the RASS score upon arrival to the PACU differed significantly between the two groups (P = 0.006). Re-sedation in the PACU was observed in 11 (22%) of the patients in the remimazolam group., Conclusions: Remimazolam-based total intravenous anesthesia with flumazenil reversal may be effective in reducing emergence time, but a significant incidence of re-sedation was observed in the PACU. Further studies are needed to determine adequate dose and timing of routine flumazenil use and minimize the risk of re-sedation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA) system. However, it remains unknown whether flumazenil (FMZ), a GABA type A receptor (GABAAR) antagonist, can reverse MFA toxicity., Methods: The behavioral and neurophysiological effects of MFA were investigated in mice with and without FMZ pre-treatment. The elevated zero maze (EZM) and marble burying tests were used to assess anxiety-like behaviors and burying activities, respectively. The standard bar test was used to evaluate catalepsy, while the actophotometer test was used to measure locomotor activity. Seizure intensity was scored, and fatalities were counted., Results: Without FMZ pre-treatment, MFA induced behavioral and neurophysiological effects in a dose-dependent manner as follows: At a dose of 20 mg/kg, i.p, MFA-treated mice exhibited anxiety-like behaviors, which was determined by a significant increase in the time spent in the closed areas and a significant decrease in the number of entries to the open areas of the EZM apparatus. These mice also showed a significant decrease in the burying activity, manifested as a significant decrease in the number of buried marbles. At 40 mg/kg, i.p., MFA-treated mice showed catalepsy that was associated with a significant decrease in locomotor activity. At a dose of 80 mg/kg, i.p., mice developed fatal tonic-clonic seizures (seizure score = 4). Pre-treatment with FMZ (5 mg/kg, i.p.) significantly reversed the anxiety-like behaviors and restored marble-burying activity. Additionally, FMZ prevented catalepsy, significantly restored locomotor activity, reduced seizure intensity (seizure score = 0.3) and significantly reduced mortalities., Conclusions: The present study's findings indicate that activation of the GABAAR is involved in the CNS toxicity of MFA, and FMZ reverses MFA toxicity by interfering with this receptor., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Introduction: Although not a potentially life-threatening poisoning, benzodiazepine (BZD) intoxication may be life-threatening in special situations/populations or those with background diseases., Areas Covered: The aim of this review is to evaluate all possible treatment options available in the literature for the management of benzodiazepine poisoning with special attention to antidote administration. We conducted a literature search using PubMed, Google Scholar, EMBASE, and Cochrane central register from 1 January 1980 to 10 November 2021 using keywords 'benzodiazepine,' 'poisoning,' 'toxicity,' 'intoxication,' and 'treatment.', Expert Opinion: Careful patient selection, ideally by a clinical toxicologist, may decrease the complications of flumazenil and add to its efficacy. The cost-to-benefit ratio should be considered in every single patient who is a candidate for flumazenil administration. In case a decision has been made to administer flumazenil, careful consideration of the possible contraindications is essential. We recommend slow administration of low doses of flumazenil (0.1 mg/minute) to avoid complications or withhold the administration with development of first signs of adverse effects. The main treatment of benzodiazepine toxicity is conservative with administration of activated charcoal, monitoring of the vital signs, prevention of aspiration and development of deep vein thrombosis due to prolonged immobilization, and respiratory support.

Background: The benzodiazepine midazolam is a γ-aminobutyric acid (GABA)-A receptor agonist frequently used for sedation or stress control in patients suffering from traumatic brain injury (TBI). However, experimental studies on benzodiazepines have reported divergent results, raising concerns about its widespread use in patients. Some studies indicate that benzodiazepine-mediated potentiation of GABAergic neurotransmission is detrimental in brain-injured animals. However, other experimental investigations demonstrate neuroprotective effects, especially in pretreatment paradigms. This study investigated whether single-bolus midazolam administration influences secondary brain damage post-TBI., Methods: Two different midazolam dosages (0.5 and 5 mg/kg BW), a combination of midazolam and its competitive antagonist flumazenil, or vehicle solution (NaCl 0.9%) was injected intravenously to mice 24 h after experimental TBI induced by controlled cortical impact. Mice were evaluated for neurological and motor deficits using a 15-point neuroscore and the rotarod test. Histopathological brain damage and mRNA expression of inflammatory marker genes were analyzed using quantitative polymerase chain reaction three days after insult., Results: Histological brain damage was not affected by posttraumatic midazolam administration. Midazolam impaired functional recovery, and this effect could not be counteracted by administering the midazolam antagonist flumazenil. An increase in IL-1β mRNA levels due to postinjury application of midazolam was reversible by flumazenil administration. However, other inflammatory parameters were not affected., Conclusions: This study merely reports minor effects of a postinjury midazolam application. Further studies focusing on a time-dependent analysis of posttraumatic benzodiazepine administration are required., (© 2022. The Author(s).)

Background: The estimated annual prevalence of drug use disorders is as high as 3%, underpinning the need to continually develop more effective treatments. Central nervous system dysregulation, contributing to acute and post-withdrawal syndromes, has traditionally been managed with benzodiazepines; however, a small but growing body of data indicate that the GABA A receptor antagonist, flumazenil, may offer some advantages over traditional management., Aim: To review the literature on the safety and efficacy of flumazenil in benzodiazepine use disorders and identify gaps in the literature., Method: A systematic method was used to identify randomised control trials. Where randomised control trials existed, non-randomised control trials were included to supplement findings., Results: Eleven flumazenil trials were included with varying doses, frequencies and routes of administration. The evidence for flumazenil alone showed generally a reduction in withdrawal symptoms with the exception of one study where withdrawal symptoms initially increased. Flumazenil plus benzodiazepine tapering was assessed in one randomised control trial and a series of non-randomised control trials. Randomised control trial results showed that flumazenil plus benzodiazepine tapering was superior at reducing withdrawal symptoms compared to benzodiazepine tapering alone and placebo. Flumazenil was associated with no serious adverse events; however there remains a risk of seizures., Conclusion: Although flumazenil shows promising efficacy in the management of benzodiazepine use disorders and withdrawal, more randomized control trials are required before a definitive recommendation can be made around its use.

The aim was to evaluate the diuretic and neuropharmacological actions of d-pinitol and describe a possible mechanism of action. The diuretic effects of d-pinitol were evaluated using mice placed in metabolic cages. The sedative, anxiolytic-like, antidepressant-like, and anticonvulsant effects of 1-100 mg/kg d-pinitol were assessed. The possible mechanisms of action of the anxiolytic-like, antidepressant-like, and anticonvulsant effects of d-pinitol were evaluated using inhibitors. d-pinitol lacked diuretic effects. However, d-pinitol showed the highest anxiolytic-like actions (ED 50  = 70 mg/kg p.o. in mice) in the cylinder exploratory test and the highest antidepressant-like activity in the forced swimming test (ED 50  = 26 mg/kg p.o. in mice). d-pinitol (100 mg/kg) exerted anticonvulsant actions in the pentylenetetrazole-induced seizures test. The pre-treatment with 2 mg/kg flumazenil reverted the anxiolytic-like actions and the anticonvulsant effects of d-pinitol, whereas the pre-treatment with 1 mg/kg yohimbine and 0.05 mg/kg prazosin abolished the antidepressant effects of d-pinitol. PRACTICAL APPLICATIONS: d-pinitol (3-O-methyl-d-chiro-inositol) is a polyol found in many fruits, as well as in many members of the Leguminosae and Fabaceae families. The results propose that this compound could contribute in the treatment of anxiety, depression, and convulsions. The findings suggest the possible participation of the GABAergic system in the anxiolytic-like and anticonvulsant actions of d-pinitol, whereas the noradrenergic system is probably involved in the antidepressant effects of d-pinitol. This study provides new information about other pharmacological uses for d-pinitol., (© 2019 Wiley Periodicals, Inc.)

The effects of the 5-HT 1A receptor blocker pindolol and the 5-HT releasing and uptake blocking agent d-fenfluramine, both used as indirect serotonin agonists, on flumazenil-induced acute anxiety reactions were studied in panic disorder patients to test the hypothesis that serotonin (5-HT) inhibits neural systems mediating panic attacks. Thirty never treated or drug free PD patients (16 females) aged 22-49 y (mean ± SD, 32.9 ± 8) received single doses of d-fenfluramine (n = 10; 30 mg, p.o.), pindolol (n = 10; 5 mg, p.o.), or placebo (n = 10) 90 and 45 min before a challenge test with flumazenil (1.5 mg, i.v., in 10 min), under double-blind conditions. Panic attacks occurred in 5 control subjects (placebo-flumazenil group), 5 subjects in the pindolol group and in 7 in the d-fenluramine pre-treated patients. Patients experiencing anxiety attacks following flumazenil reported higher increases in anxiety scores. Respiratory rate increases were not different between patients experiencing or not a panic attack. Despite sample size limitation, this study suggests that flumazenil induced anxiety reaction is not a good pharmacological model of panic attacks, considering the absence of serotonergic modulation of its effects., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Midazolam sedation during elective endoscopy is widely performed and flumazenil is frequently administered after endoscopy to reverse sedation in clinical practice. This study aimed to investigate the safety and efficacy of flumazenil injections after elective endoscopy under midazolam sedation., Methods: Participants who underwent an upper endoscopy under midazolam sedation were randomly divided into two groups. In group I, flumazenil was administered i.v. 10 min after the patient's transfer to the recovery room, and no antidote was injected in group II. The time of stay in the recovery room and adverse events were reviewed through the nursing records. We asked the patients about their pain and degree of satisfaction according to a visual analogue scale (VAS), their memory of the procedure, mental status and the presence of uncomfortable symptoms on the day of the procedure and the day afterwards., Results: The length of stay in recovery was significantly shorter in group I than in group II. No significant differences were found in the number of patients with pain (VAS ≥1), adverse events and discomfort between the two groups. Additionally, there were no differences in the patients' memory of the procedure, satisfaction with sedation, willingness to repeat the endoscopy and mental status., Conclusions: The time in the recovery room after flumazenil administration was significantly shortened, and the use of the drug did not increase the risk of adverse events or discomfort. The use of flumazenil for reversing midazolam sedation seems to be safe and effective., (© 2018 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Introduction: Flumazenil is an antagonist of the GABA/benzodiazepines receptor complex that might play a role in the treatment of hepatic encephalopathy. However, its efficacy and safety are a matter of debate., Methods: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach., Results and Conclusions: We identified two systematic reviews including fourteen randomized trials. We concluded flumazenil does not reduce mortality in patients with hepatic encephalopathy and it is not clear whether it leads to any clinical improvement because the certainty of the evidence is very low.

Background: Hepatic encephalopathy is a common complication of cirrhosis which results in poor brain functioning. The spectrum of changes associated with hepatic encephalopathy ranges from the clinically 'indiscernible' or minimal hepatic encephalopathy to the clinically 'obvious' or overt hepatic encephalopathy. Flumazenil is a synthetic benzodiazepine antagonist with high affinity for the central benzodiazepine recognition site. Flumazenil may benefit people with hepatic encephalopathy through an indirect negative allosteric modulatory effect on gamma-aminobutyric acid receptor function. The previous version of this review, which included 13 randomised clinical trials, found no effect of flumazenil on all-cause mortality, based on an analysis of 10 randomised clinical trials, but found a beneficial effect on hepatic encephalopathy, based on an analysis of eight randomised clinical trials., Objectives: To evaluate the beneficial and harmful effects of flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy., Search Methods: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and LILACS; meeting and conference proceedings; and bibliographies in May 2017., Selection Criteria: We included randomised clinical trials regardless of publication status, blinding, or language in the analyses of benefits and harms, and observational studies in the assessment of harms., Data Collection and Analysis: Two review authors extracted data independently. We undertook meta-analyses and presented results using risk ratios (RR) with 95% confidence intervals (CI) and I 2 values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary Group domains; determined the quality of the evidence using GRADE; evaluated the risk of small-study effects in regression analyses; and conducted trial sequential, subgroup, and sensitivity analyses., Main Results: We identified 14 eligible randomised clinical trials with 867 participants, the majority of whom had an acute episode of overt hepatic encephalopathy. In addition, we identified one ongoing randomised clinical trial. We were unable to gather outcome data from two randomised clinical trials with 25 participants. Thus, our analyses include 842 participants from 12 randomised clinical trials comparing flumazenil versus placebo. We classified one randomised clinical trial at low risk of bias in the overall assessment and the remaining randomised clinical trials at high risk of bias. The duration of follow-up ranged from a few minutes to two weeks, but it was less than one day in the majority of the trials.In total, 32/433 (7.4%) participants allocated to flumazenil versus 38/409 (9.3%) participants allocated to placebo died (RR 0.75, 95% CI 0.48 to 1.16; 11 randomised clinical trials; low quality evidence). The Trial Sequential Analysis and the one randomised clinical trial assessed as low risk of bias (RR 0.76, 95% CI 0.37 to 1.53) found no beneficial or harmful effects of flumazenil on all-cause mortality. The methods used to evaluate hepatic encephalopathy included several different clinical scales, electrophysiological variables, and psychometric tests. Flumazenil was associated with a beneficial effect on hepatic encephalopathy when including all randomised clinical trials (RR 0.75, 95% CI 0.71 to 0.80; 824 participants; nine randomised clinical trials; low quality evidence), or just the trial at low risk of bias (RR 0.78, 95% CI 0.72 to 0.84; 527 participants). The Trial Sequential Analysis supported a beneficial effect of flumazenil on hepatic encephalopathy. The randomised clinical trials included little information about causes of death and little information on non-fatal serious adverse events., Authors' Conclusions: We found low quality evidence suggesting a short-term beneficial effect of flumazenil on hepatic encephalopathy in people with cirrhosis, but no evidence of an effect on all-cause mortality. Additional evidence from large, high quality randomised clinical trials is needed to evaluate the potential benefits and harms of flumazenil in people with cirrhosis and hepatic encephalopathy.

Benzodiazepines (BZDs) are highly effective to suppress various types of seizures; however, their clinical use is limited due to adverse effects and tolerance and dependence liability. Drugs that act only as partial agonists at the BZD recognition site (initially termed "BZD receptor") of the GABAA receptor chloride ionophore complex or exhibit a GABAA receptor subtype-selectivity are thought to have advantages vs. full agonists such as diazepam and most other clinically used BZDs in that such compounds have less adverse effects and reduced or absent tolerance and dependence liability. One of such compounds, abecarnil, has been clinically evaluated as a novel anxiolytic drug, but, despite its potent preclinical anti-seizure activity, it has not yet been evaluated in patients with epilepsy. In the present proof-of-concept study, we performed a within-subject placebo-controlled, single oral dose study of abecarnil in patients with photosensitive epilepsy. Flumazenil, which is generally considered a BZD receptor antagonist, but has slight partial agonistic properties, was used for comparison. In total, 12 patients were enrolled in this study. Abecarnil, 5 or 10mg, completely abolished the photo-paroxysmal EEG response, while flumazenil, 30, 60 or 100mg, was less effective. The anti-epileptic effect of abecarnil was significantly different from both placebo and flumazenil. Sedative adverse effects were observed after abecarnil but not flumazenil. The study substantiates previous pre-clinical experiments that abecarnil exerts pronounced anti-seizure activity. Epilepsy is often associated with anxiety, so that the anxiolytic activity of abecarnil would be an added advantage when using this compound in epilepsy patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Flumazenil is used for the reversal of benzodiazepine overdose. Serious adverse events (SAEs) including seizures and cardiac arrhythmias have been reported in patients treated with flumazenil, and the clinical advantage of flumazenil treatment has been questioned. The objective was to assess the risk of (S)AEs associated with the use of flumazenil in patients with impaired consciousness due to known or suspected benzodiazepine overdose. Studies included in the meta-analyses were identified by literature search in Medline, Cochrane Library and Embase using combinations of the words flumazenil, benzodiazepines, anti-anxiety agents, poisoning, toxicity and overdose. Randomised clinical trials (RCTs) in verified or suspected benzodiazepine overdose patients comparing treatment with flumazenil versus placebo were included. Pre-defined outcome measures were AEs, SAEs and mortality. Thirteen trials with a total of 994 randomised (990 evaluable) patients were included. AEs were significantly more common in the flumazenil group (138/498) compared with the placebo group (47/492) (risk ratio: 2.85; 95% confidence interval: 2.11-3.84; p < 0.00001). SAEs were also significantly more common in the flumazenil group compared with the placebo group (12/498 versus 2/492; risk ratio: 3.81; 95% CI: 1.28-11.39; p = 0.02). The most common AEs in the flumazenil group were agitation and gastrointestinal symptoms, whereas the most common SAEs were supraventricular arrhythmia and convulsions. No patients died during the blinded phase of the RCTs. The use of flumazenil in a population admitted at the emergency department with known or suspected benzodiazepine intoxication is associated with a significantly increased risk of (S)AEs compared with placebo. Flumazenil should not be used routinely, and the harms and benefits should be considered carefully in every patient., (© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Flumazenil is an effective benzodiazepine (BZD) antagonist. Empiric use of flumazenil in the emergency department (ED) is not widely recommended due to concerns of seizures, which are commonly associated with coingestants and BZD withdrawal., Objective: The objective of the study is to assess adverse events and clinical outcomes of flumazenil administration in known and suspected BZD overdose in an ED at a tertiary academic medical center., Methods: This is a retrospective observational study of adult patients administered flumazenil for known or suspected BZD overdose in the ED over 7 years. Outcomes included mental status improvement, the incidence of seizures, and intubation of the trachea after flumazenil administration., Results: Twenty-three patients were included in the analysis, of which 15 (65%) of patients experienced some type of clinically significant mental status improvement. No seizures were identified despite 7 (35%) reported proconvulsant coingestants. One patient required intubation of the trachea but was subsequently extubated in the ED., Conclusions: A majority of patients had improved mental status after the administration of flumazenil. No patient experienced seizures. Additional studies that clarify the role of flumazenil for ED patients with suspected BZD toxicity are warranted., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This review paper discusses the central role of gamma-aminobutyric acid (GABA) in diverse physiological systems and functions and the therapeutic potential of the benzodiazepine antagonist flumazenil (Ro 15- 1788) for a wide range of disorders of the central nervous system (CNS). Our group and others have studied the potential of flumazenil as a treatment for benzodiazepine dependence. A small but growing body of research has indicated that flumazenil may also have clinical application in CNS disorders such as Parkinson's disease, idiopathic hypersomnia and amyotrophic lateral sclerosis. Despite this body of research the therapeutic potential of flumazenil remains poorly understood and largely unrealized. The purpose of this paper is not to provide an exhaustive review of all possible therapeutic applications for flumazenil but rather to stimulate research interest, and discussion of the exciting therapeutic potential of this drug for a range of chronic debilitating conditions.

Both alcohol withdrawal syndrome (AWS) and benzodiazepines can cause delirium. Benzodiazepine-associated delirium can complicate AWS and prolong hospitalization. Benzodiazepine delirium can be diagnosed with flumazenil, a GABA-A receptor antagonist. By reversing the effects of benzodiazepines, flumazenil is theorized to exacerbate symptoms of AWS and precludes its use. For patients being treated for alcohol withdrawal, flumazenil can diagnose and treat benzodiazepine delirium without precipitating serious or life-threatening adverse events. Hospital admission records were retrospectively reviewed for patients with the diagnosis of AWS who received both benzodiazepines and flumazenil from December 2006 to June 2012 at a university-affiliated inpatient toxicology center. The day of last alcohol consumption was estimated from available blood alcohol content or subjective history. Corresponding benzodiazepine, flumazenil, and adjunctive sedative pharmacy records were reviewed, as were demographic, clinical course, and outcome data. Eighty-five patients were identified (average age 50.3 years). Alcohol concentrations were detectable for 42 patients with average 261 mg/dL (10-530 mg/dL). Eighty patients were treated with adjunctive agents for alcohol withdrawal including antipsychotics (n = 57), opioids (n = 27), clonidine (n = 35), and phenobarbital (n = 23). Average time of flumazenil administration was 4.7 days (1-11 days) after abstinence, and average dose was 0.5 mg (0.2-1 mg). At the time of flumazenil administration, delirium was described as hypoactive (n = 21), hyperactive (n = 15), mixed (n = 41), or not specified (n = 8). Response was not documented in 11 cases. Sixty-two (72.9 %) patients had significant objective improvement after receiving flumazenil. Fifty-six patients required more than one dose (average 5.6 doses). There were no major adverse events and minor adverse effects included transiently increased anxiety in two patients: 1 patient who received 0.5 mg on abstinence day 2 and another patient who received 0.2 mg flumazenil on abstinence day 11. This is the largest series diagnosing benzodiazepine delirium after AWS in patients receiving flumazenil. During the treatment of AWS, if delirium is present on day 5, a test dose of flumazenil may be considered to establish benzodiazepine delirium. With the limited data set often accompanying patients with AWS, flumazenil diagnosed benzodiazepine delirium during the treatment of AWS and improved impairments in cognition and behavior without serious or life-threatening adverse events in our patients.

Unlabelled: Studies report that (11)C-flumazenil (FMZ) PET more specifically localizes the epileptogenic zone in patients with medically refractory focal epilepsy than (18)F-FDG PET. However, practical aspects of (11)C use limit clinical application. We report a phase I/IIa study assessing the clinical use of (18)F-FMZ PET for the localization of the epileptogenic zone in patients with drug-resistant temporal lobe epilepsy (TLE). Receptor binding was quantified using kinetic modeling that did not require arterial sampling., Methods: Dynamic (18)F-FMZ PET and static interictal (18)F-FDG PET scans were compared in healthy controls (n = 17 for (18)F-FMZ and n = 20 for (18)F-FDG) and TLE patients with mesial temporal sclerosis on MR imaging (MTS, n = 12) and with normal MR imaging (NL TLE, n = 19). Masked visual assessment of images was undertaken. Parametric images of (18)F-FMZ binding potential (BPND) were generated using the simplified reference tissue model. Region-of-interest analysis on coregistered MR images and statistical parametric mapping were used to quantify (18)F-FMZ BPND and (18)F-FDG uptake in the temporal lobe., Results: The visual assessment of static standardized uptake value images showed (18)F-FMZ PET to have high specificity (16/17 [94%]) and moderate sensitivity (21/31 [68%]) for the localization of the epileptogenic zone, with a more restricted abnormality than (18)F-FDG PET. However, the (18)F-FMZ standardized uptake value images were falsely localizing in 3 of 31 patients (10%). Region-of-interest analysis demonstrated reductions in ipsilateral hippocampal (18)F-FMZ BPND in patients with either MTS or NL TLE, compared with controls subjects. Ipsilateral hippocampal (18)F-FMZ BPND was independent of both hippocampal volume and (18)F-FDG uptake, whereas ipsilateral hippocampal volume was correlated with (18)F-FDG uptake (r(2) = 0.69, P < 0.0001). Statistical parametric mapping analysis demonstrated decreased uptake in 14 of 31 (45%) cases with (18)F-FMZ PET and 18 of 29 (62%) with (18)F-FDG PET. Cluster size was significantly smaller on (18)F-FMZ than (18)F-FDG images (37 vs. 160 voxels, P < 0.01)., Conclusion: (18)F-FMZ PET has potential as a clinical tool for the localization of the epileptogenic zone in the presurgical evaluation of drug-resistant TLE, providing information complementary to (18)F-FDG PET, with a more restricted region of abnormality.

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.

Background: The frequency of seizures among acutely poisoned adults who are administered flumazenil has not been well established., Study Objective: The objectives of the study were: to determine the frequency of seizures among acutely poisoned adults administered flumazenil; to identify factors associated with seizures; and to determine the mental status of subjects before and after administration of flumazenil., Methods: This study was a historical case series of acutely poisoned adults reported to a poison control system from 1999 to 2008. Included cases were those involving administration of flumazenil to subjects who were ≥ 18 years of age. Both genders were included. Variables collected included: presence of seizure or death, exposure to a pro-convulsant drug, and mental status before and after flumazenil administration., Results: Over the 10-year period studied, 904 cases were identified that met inclusion criteria. Thirteen subjects (1.4%) developed seizures after flumazenil was administered. One death occurred. There were 293 subjects exposed to a pro-convulsant drug, and 8 of these had seizures after flumazenil administration. Development of seizures after flumazenil administration was significantly associated with exposure to a pro-convulsant drug (odds ratio 3.41; 95% confidence interval 1.13-10.72). Mental status before and after flumazenil administration was available for 546 subjects (60.3%). Of these, 291 (53.3%) became awake after administration of flumazenil., Conclusions: Flumazenil administration to acutely poisoned adults resulted in a low frequency of seizures and death. Development of seizures was associated with exposure to a pro-convulsant drug. More than half of the subjects for whom mental status was recorded became awake after receiving flumazenil., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Benzodiazepine (BZD) overdose (OD) continues to cause significant morbidity and mortality in the UK. Flumazenil is an effective antidote but there is a risk of seizures, particularly in those who have co-ingested tricyclic antidepressants. A study was undertaken to examine the frequency of use, safety and efficacy of flumazenil in the management of BZD OD in the UK., Methods: A 2-year retrospective cohort study was performed of all enquiries to the UK National Poisons Information Service involving BZD OD., Results: Flumazenil was administered to 80 patients in 4504 BZD-related enquiries, 68 of whom did not have ventilatory failure or had recognised contraindications to flumazenil. Factors associated with flumazenil use were increased age, severe poisoning and ventilatory failure. Co-ingestion of tricyclic antidepressants and chronic obstructive pulmonary disease did not influence flumazenil administration. Seizure frequency in patients not treated with flumazenil was 0.3%. The frequency of prior seizure in flumazenil-treated patients was 30 times higher (8.8%). Seven patients who had seizures prior to flumazenil therapy had no recurrence of their seizures. Ventilation or consciousness improved in 70% of flumazenil-treated patients. Flumazenil administration was followed by one instance each of agitation and brief seizure., Conclusions: Flumazenil is used infrequently in the management of BZD OD in the UK. It was effective and associated with a low incidence of seizure. These results compare favourably with the results of published randomised controlled trials and cohort studies, although previous studies have not reported the use of flumazenil in such a high-risk population. This study should inform the continuing review of national guidance on flumazenil therapy.

Objective: The goal of this retrospective cohort study of pediatric patients exposed to flumazenil was to identify the frequency of seizures., Methods: Included patient were those aged 12 years or younger who received flumazenil, who had evidence of clinical poisoning as defined by an altered mental status, and who were reported to the California Poison Control System for the period 1999 to 2008. Data variables were age, sex, seizure, death, acute exposure to a benzodiazepine, drugs of exposure, long-term use of benzodiazepines, history of a seizure disorder, mental status before flumazenil administration, and poison center recommendation of flumazenil (yes/no)., Results: Eighty-three patients were included. Forty-eight (58%) of this subset were female. Median age was 2 years (range, 3 months-12 years). Seventy (84%) patients were younger than 5 years. Of the 83 patients, 68 (82%) were allegedly exposed to a benzodiazepine; whereas, 12 (15%) had been allegedly exposed to a proconvulsant drug. No flumazenil-related seizures occurred (0% with 95% confidence interval, 0%-4%). The California Poison Control System recommended flumazenil use in 60 (72%) of the 83 cases, and 48 of these had been allegedly exposed to a benzodiazepine., Conclusions: No flumazenil-associated seizures occurred among allegedly benzodiazepine- and non-benzodiazepine-poisoned pediatric patients aged 12 years or younger.

Aims: To evaluate the efficacy and safety of the PROMETA™ Protocol for treating methamphetamine dependence., Design: A double-blind, placebo-controlled 108-day study with random assignment to one of two study conditions: active medication with flumazenil (2 mg infusions on days 1, 2, 3, 22, 23), gabapentin (1200 mg to day 40) and hydroxazine (50 mg to day 10) versus placebo medication (with active hydroxazine only)., Setting: Three substance abuse treatment clinics: two in-patient, one out-patient., Participants: Treatment-seeking, methamphetamine-dependent adults (n = 120)., Measurements: Primary outcome was percentage of urine samples testing negative for methamphetamine during the trial., Findings: No statistically significant between-group differences were detected in urine drug test results, craving, treatment retention or adverse events., Conclusions: The PROMETA protocol, consisting of flumazenil, gabapentin and hydroxyzine, appears to be no more effective than placebo in reducing methamphetamine use, retaining patients in treatment or reducing methamphetamine craving., (© 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Dysrhythmias, although common in overdose situations, are not often seen after benzodiazepine exposures. We report two cases of transient atrioventricular block after benzodiazepine misuse. Case 1 is a 4-year-old boy who was found unresponsive after an ingestion of clonazepam. An electrocardiogram (EKG) performed on emergency department presentation demonstrated first-degree atrioventricular block (PR 206 ms). After flumazenil administration, he developed second-degree atrioventricular block (Mobitz Type 1). EKG abnormalities resolved by morning. Serum clonazepam was 478 ng/mL (laboratory clonazepam reference range, 10-75 ng/mL with a dose of up to 6 mg/day) 5 hours after being found unresponsive. Case 2 is a 23-year-old man who presented to the emergency department after ingesting risperidone, combination hydrocodone/acetaminophen, and alprazolam. On arrival, his EKG demonstrated sinus bradycardia with a PR interval of 182 msec. He subsequently developed second-degree atrioventricular block (Mobitz Type I). Sinus bradycardia with resolution of his atrioventricular block (PR 200 ms) was seen on a third EKG performed 5 hours after presentation. These two patients demonstrated transient first- and second-degree atrioventricular block after benzodiazepine exposure. Benzodiazepines have been shown to alter L-type Ca2+ channel function. This alteration in function may account for the dysrhythmias seen in our patients. Together, these cases serve to remind clinicians of this rare but potentially serious complication associated with benzodiazepine exposure.

We describe a patient with chronic myelogenous leukemia (CML) who developed drug-induced agranulocytosis. A 75-year-old female was diagnosed with CML in December 2001. She had been receiving imatinib therapy for more than five years. In August 2007, she was hospitalized due to a severe neutropenia 10 days after colonoscopy. She was diagnosed as having agranulocytosis induced by colonoscopy premedication including scopolamine butylbromide and flumazenil. Severe neutropenia was resolved by G-CSF treatment without CML progression. Agranulocytosis in patients with CML is rare, but potentially lethal. Here, we report the clinical course in this patient.

Drug use has been associated with craving, which may be described as a powerful and sometimes overwhelming urge to use the drug. Patients seeking treatment for methylamphetamine dependence must cope with drug cravings as they engage in psychosocial treatments. Changes in brain GABA(A) receptors during substance use and withdrawal provide a neurobiological basis for craving and associated anxiety. Flumazenil (a benzodiazepine antagonist) plus gabapentin (an antiepileptic) were compared with placebo in a randomized, double-blind study to assess the effects on craving during initial treatment for methylamphetamine dependence. Evaluation was conducted over a 30-day period. Craving and drug use were found to be highly correlated. Craving was reduced significantly in the flumazenil plus gabapentin group compared with placebo following the initial treatment period and throughout the 30 days. Decreased methylamphetamine use was also observed, as measured by urine drug screens and self-reports.

Flumazenil is one of imidazo-benzodiazepine (Anexate) which has been generally used as benzodiazepine competitive antagonist for the treatment of benzodiazepine intoxication during recent decades. Some has recommended diagnostic usage in ICU as well, for suspected benzodiazepine intoxicated cases. In this study we present a patient intoxicated with lorazepam who developed a ventricular tachycardia after receiving flumazenil as therapeutic mean, though the attack was appropriately terminated by administration of a bolus dose of Amiodarone. We believe that the ventricular tachycardia onset in above mentioned case is secondary to Flumazenil administration in susceptible patient with previous history of ischemic heart disease. Ventricular tachycardia has rarely reported as flumazenil side effects.

Background: TEE is a semi-invasive tool broadly used and its utilization associated to sedatives drugs might to affect the procedure safety., Objective: to analyze aspects of TEE safety associated to the use of Midazolan (MZ) and Flumazenil (FL) and the influence of the clinical variables on the event rate., Method: prospective study with 137 patients that underwent TEE with MZ associated to moderate sedation. We analyzed the following events: complications related with the topical anesthesia, with MZ use and with the procedure. Uni- and multivariate analyses were used to test the influence of the clinical variables: age, sex, stroke, myocardiopathy (MP), duration of the test, mitral regurgitation (MR) and the MZ dose., Results: All patients (65+/-16 yrs; 58% males) finished the examination. The mean doses of MZ and FL were 4.3+/-1.9 mg and 0.28+/-0.2 mg, respectively. The duration of the examination and the mean ejection fraction (EF) were 16.4+/-6.1 minutes and 60+/-9%, respectively. Mild hypoxia (SO2<90%) was the most common event (11 patients); 3 patients (2%) presented transient hypoxia due to upper airway obstruction by probe introduction and 8 (5.8%) due to hypoxia caused by MZ use. Transient hypotension (SAP<90mmHg) occurred in 1 patient (0.7%). The multivariate analysis showed that severe MR, MP (EF<45%) and high doses of MZ (>5mg) were associated with events (p<0.001). The EF was 40%, in the group with MP and 44% in the group with severe MR and it can be a factor associated with clinical events in the last group., Conclusion: TEE with sedation presents a low rate of events. There were no severe events and there was no need to interrupt the examinations.

Improved treatment of alcohol dependence is a high priority, including defining subtypes that might respond differently. We evaluated a medication combination of intravenous flumazenil (FMZ) and oral gabapentin (GBP) in alcoholics who did and did not exhibit pretreatment alcohol withdrawal (AW) symptoms. Sixty alcohol-dependent individuals (44 with low AW and 16 with high AW) were randomized to receive FMZ (2 mg of incremental bolus for 20 minutes for 2 consecutive days) and GBP (up to 1200 mg nightly for 39 days) or their inactive placebos. Alcohol withdrawal was measured for the first 2 days, and drinking, sleep parameters, and adverse events were monitored during weekly evaluations, along with behavioral counseling sessions. Percent days abstinent (PDA) during treatment and time to first heavy drinking (TFHD) day were primary outcome variables. There was an interaction between the pretreatment AW status and the medication group on PDA (P = 0.0006) and TFHD (P = 0.06). Those in the high AW group had more PDA and more TFHD if treated with active medications, whereas those in the low AW group had more PDA and more TFHD if treated with placebo. This interaction remained for those totally abstinent (P = 0.03) and was confirmed by percent carbohydrate-deficient transferrin values. In addition, the pattern of response remained up to 8 weeks after treatment. In addition, in those with high AW, greater improvement in AW symptoms was observed in the active medication group compared with the placebo group. These results suggest a differential response to FMZ/GBP treatment, depending on pretreatment AW status that should be taken into account during future treatment trials.

Flumazenil is a benzodiazepine antagonist. It is widely used as an antidote in comatose patients suspected of having ingested a benzodiazepine overdose. Flumazenil is known to induce cardiac arythmias and seizures, in part because of drug interactions. We present a 75-year-old woman, who was brought to the Emergency Department with a drug overdose following a suicide attempt. She developed generalized seizures shortly after the administration of flumazenil.

There is a need for novel anxiolytics, which are effective, but do not cause sedation, tolerance, and rebound anxiety on discontinuation. To investigate a procedure that can be used to assess these characteristics preclinically, rats were initially trained to press a lever at a high rate to obtain food. Once trained, periods of punishment were introduced in which electric shocks were superimposed. The intensity of these electric shocks was increased every 90 s from very low (0.01 mA) to sufficiently high to stop most subjects responding (0.4 mA), so that a complete rate/intensity function was obtained during each punishment period. The benzodiazepine, chlordiazepoxide, and two novel subtype-selective gamma-aminobutyric acid-A agonists, TP003 and TPA023, significantly increased response rates mildly suppressed by intermediate levels of electric shock without any effect on unpunished response rate. Two clinically anxiogenic agents, yohimbine and flumazenil, reduced the rate of punished responding. Aripiprazole and amphetamine reduced both punished and unpunished responding. Repeated treatment with diazepam 2.5 mg/kg daily for 15 days, initially markedly reduced unpunished response rates, but also increased punished response rates, an effect which became greater with repeated treatment. Abrupt cessation of diazepam treatment produced a reduction in punished responding. Diazepam (5 mg/kg daily) produced a greater reduction in unpunished responding, a smaller increase in punished responding, and a larger and longer lasting reduction in punished rates on withdrawal. In conclusion, the procedure detected anxiolytic and anxiogenic effects of drugs, and the sedative side effects, development of tolerance, and rebound-anxiety on discontinuation of a benzodiazepine. This procedure should have utility in the characterization of novel treatments of anxiety.

An 83-year-old female patient was managed in intensive care unit postoperatively with artificial ventilation and propofol-based sedation. On the second postoperative day, we tried to remove an endotracheal tube. Naloxone was administered to the patient for reversing the sedative effect of fentanyl infused intraoperatively. Her consciousness level was improved; however, subsequent administration of flumazenil induced hypnosis. Benzodiazepine-like partial agonistic effect of flumazenil might have enhanced residual hypnotic effect of propofol. Administration of flumazenil to the patient infused with propofol should be done cautiously for awakening the patient from anesthesia.

Flumazenil is a short-acting intravenously administered gamma-aminobutyric acid (GABA) antagonist used to reverse the effects of benzodiazepines. Based upon current basal ganglion models in Parkinson's disease (PD), flumazenil could normalize neuronal signaling at several different locations. We conducted a double-blind, placebo controlled, single dose, cross-over trial of flumazenil and placebo in 16 subjects with PD. Subjects were primarily assessed with serial tapping tests (1 minute for each hand) at 15-minute intervals for 90 minutes after infusion. Secondary assessments included the Unified Parkinson's Disease Rating Scale (UPDRS) Motor part at baseline and 45 minutes after infusion, and global impressions. Subjects then underwent a 90-minute washout and entered the opposite arm of the cross-over. Change in tapping speed compared to baseline improved throughout the 90-minute period (P < 0.0001) and at each individual time (P < 0.01), except for 15 minutes status after infusion, with flumazenil compared to placebo. UPDRS scores tended to improve more on drug, but this finding was not significant. The medication was well tolerated. The most common adverse event on drug was a sense of "light-headedness" or "dizziness." GABA antagonists represent a novel potential treatment class for PD.

Benzodiazepines are an important class of drugs in the management of acute pediatric seizure disorders such as status epilepticus. They are used both in the community and in the hospital; however, one of their major side effects is respiratory depression. If ventilation is needed for benzodiazepine-induced respiratory depression during seizure management, pressures to facilitate extubation may lead to the use of the specific reversal agent for this class of drugs, flumazenil. Three cases of seizure recurrence after flumazenil use in this context are reported, and the pharmacology is discussed. Irrespective of pressure to extubate such children, physicians must be alert to the potential risk of flumazenil in the clinical scenario.

In South Africa Rhus pyroides is traditionally used in the treatment of epilepsy. In the present study two biflavonoids with activity in the (3)H-Ro 15-1788 (flumazenil) binding assay were isolated by high pressure liquid chromatography (HPLC) fractionation of the ethanol extract of the leaves from Rhus pyroides. The structures of the two biflavonoids were elucidated by nuclear magnetic resonance spectroscopy (NMR) to be agathisflavone and amentoflavone. Agathisflavone and amentoflavone competitively inhibited the binding of (3)H-Ro 15-1788 with a K(i) of 28 and 37 nM, respectively. Extracts of Rhus dentata and Rhus pentheri were not as active as the extract from Rhus pyroides; both were found to contain apigenin and agathisflavone. The monomer apigenin, agathisflavone and amentoflavone were fitted into a pharmacophore model for ligands binding to the GABA(A) receptor benzodiazepine site. This reflected the affinities of the compounds in the [(3)H]-flumazenil binding assay.

Purpose: Ataxia, sedation, amnesia, ethanol and barbiturate potentiation, loss of efficacy (tolerance), development of dependence, and the potential for drug abuse limit the clinical use of benzodiazepines (BZDs) for long-term treatment of epilepsy or anxiety. BZD ligands that are in current use act as full allosteric modulators of gamma-aminobutyric acid (GABA)-gated chloride channels and, on long-term administration, trigger a functional uncoupling between the GABAA and BZD recognition sites. Partial allosteric modulators, which have a low intrinsic activity at the BZD recognition site of the GABAA receptor, might eventually overcome the limitations of full agonists such as diazepam (DZP)., Methods: In the present study, the new low-affinity partial BZD-receptor agonist ELB 138 [former name AWD 131-138; 1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one] was evaluated in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures., Results: ELB 138 was shown to increase potently the pentylenetetrazole (PTZ) seizure threshold in dogs. Prolonged oral administration with twice-daily dosing of ELB 138 with either 5 or 40 mg/kg over a 5-week period was not associated with loss of anticonvulsant efficacy in the PTZ dog model. To study whether physical dependence developed during long-term treatment, the BZD antagonist flumazenil was injected after 5 weeks of treatment with ELB 138. Compared with prolonged treatment with DZP, only relatively mild abstinence symptoms were precipitated in dogs treated with ELB 138, particularly at the lower dosage (5 mg/kg, b.i.d.). In a prospective trial in dogs with newly diagnosed epilepsy, ELB 138 markedly reduced seizure frequency and severity without significant difference to standard treatments (phenobarbital or primidone) but was much better tolerated than the standard drugs. In dogs with chronic epilepsy, most dogs exhibited a reduction in seizure frequency and severity during add-on treatment with ELB 138., Conclusions: The data demonstrate that the partial BZD receptor agonist ELB 138 exerts significant anticonvulsant efficacy without tolerance in a dog seizure model as well as in epileptic dogs with spontaneously recurrent seizures. These data thus substantiate that partial agonism at the BZD site of GABAA receptors offers advantages versus full agonism and constitutes a valuable approach for treatment of seizures.

Flumazenil, an imidazobenzodiazepine, is the first benzodiazepine antagonist and is being used to reverse the adverse pharmacological effects of benzodiazepine. There have been a few reports on the central nevous system side effects with its use. We report a patient with generalized ballism following administration of flumazenil. The mechanism through which flumazenil induced this symptom is unknown. It is conceivable that flumazenil may antagonize the GABA-benzodiazepine receptor complex and induce dopamine hypersensitivity, thus induce dyskinesic symptoms.

Objectives: (a) To compare the use of high dose intramuscular midazolam with and without intranasal flumazenil in children after suturing. (b) To compare the use of high dose intramuscular midazolam with low dose intramuscular ketamine in children before suturing., Methods: 87 children, aged between 1 and 7 years, presenting with simple wounds needing sedation, were studied. Children considered combative (n=47) were given ketamine (2.5 mg/kg intramuscularly). The remaining 40 children were given midazolam (0.4 mg/kg intramuscularly) with and without flumazenil (25 microg/kg, intranasally)., Results: The median oxygen saturation was 97% in both midazolam groups. Flumazenil significantly reduced the amount of agitation during recovery (p=0.048) and also the time at which children were ready for discharge (median 55 versus 95 minutes, p value <0.001). After discharge both midazolam groups had an unsteady gait (75%) and there was no significant difference in the duration. As expected because of the deliberate selection of combative children into the ketamine group, the pre-sedation behaviour was slightly more disturbed compared with the midazolam group (p=0.10). However, the ketamine group was less agitated during local anaesthetic and suturing p<0.001., Conclusion: Intramuscular midazolam (0.4 mg/kg) did not effectively sedate the children, in that a significant number still had to be restrained. However, none could remember the suturing. Intranasal flumazenil seems to be effective in shortening the time to discharge. If midazolam is to be used then a dose high enough to produce full amnesia should be used, there seems to be no advantage in increasing the dose further. Low dose intramuscular ketamine remains the drug of choice.

Objective: To evaluate the efficacy of flumazenil use by a one-year survey of practice in tan emergency department., Design: During a one-year period, an observational prospective study in the emergency department of an urban community hospital enrolled every patient admitted with a history of pure or mixed benzodiazepine acute poisoning. Case records were secondarily reviewed by an expert group. Actual flumazenil use during hospitalization was compared to currently recommended indications. In order to evaluate the efficacy of flumazenil use, patients who received flumazenil were matched with those who did not and effects on mortality, morbidity, number of costly procedures (CT scan, diagnostic toxicology, etc.) and duration of hospital stay were determined., Results: Of the 1529 patients admitted in 1 year for acute poisoning, 478 reportedly ingested at least one benzodiazepine. Twenty-nine patients (6%) received flumazenil in the emergency department whereas the expert reviewers recommended flumazenil use in only 18 (3.7%). In 11/29 (38%) cases, the use of fumazenil was considered inappropriate. The expert group considered flumazenil to be contraindicated in 93 of 478 patients. Nonetheless, flumazenil was used in 11 patients (rate of potentially harmful flumazenil use: 11/93; 12%), and a severe complication occurred in one of these patients after flumazenil. No significant difference could be shown in outcome, complication rate, number of complex procedures or duration of hospital stay between patients who received flumazenil and matched patients who did not., Conclusion: The use of flumazenil in the clinical practice of an emergency department fails to show any beneficial effect in adult patients. Moreover, contraindications are frequently overlooked and this may expose patients to substantial risk of complications.