Intravenous Flumazenil Research Articles

Reversibility of alfaxalone with intravenous flumazenil in cats: a prospective study.

Introduction: This study assessed the GABAA receptor antagonist flumazenil effect on the anesthetic activity of the GABAA receptor modulator and anesthetic, alfaxalone, when administered intravenously in healthy cats.

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

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. 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. 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). 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.

The combined effects of midazolam and propofol sedation on muscle power

We performed a randomised, crossover study to investigate the effects of intravenous sedation on grip strength and bite force. Twenty male volunteers received a bolus intravenous injection of midazolam (0.02 mg.kg(-1)) together with a 30-min propofol infusion designed to achieve an effect-site concentration of 1.0 μg.ml(-1). Observed variables included bispectral index, observer's assessment of alertness/sedation, correct answer rate of Stroop colour-word test, grip strength and bite force. Grip strength decreased from a median (IQR [range]) of 483 (443-517 [380-586]) N to 358 (280-405 [108-580]) N (p < 0.001) during sedation and recovered following flumazenil administration, while bite force increased from 818 (593-1026 [405-1406]) N to 1377 (1243-1585 [836-2357]) N (p < 0.001) during sedation. Although bite force gradually returned to baseline following flumazenil administration, it remained increased throughout the experimental period. We conclude that bite force increased during intravenous sedation and that this may have clinical implications.

Intravenous flumazenil infusion to treat benzodiazepine dependence should be performed in the inpatient clinical setting for high risk of seizure

Intravenous flumazenil infusion to treat benzodiazepine dependence should be performed in the inpatient clinical setting for high risk of seizure

The Fallacy of a Lifesaving Sublingual Injection of Flumazenil

The Fallacy of a Lifesaving Sublingual Injection of Flumazenil

Efficacy of a Combination of Flumazenil and Gabapentin in the Treatment of Alcohol Dependence

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.

Effect of intravenous flumazenil on oral midazolam pharmacokinetics and pharmacodynamics for use as a cytochrome P450 3A probe

Phenotyping intestinal and hepatic cytochrome P450 (CYP) 3A activity with oral midazolam can be limited by midazolam-induced central nervous system (CNS) side effects. Determining methods to minimize CNS side effects optimizes use of midazolam as a CYP3A probe. The objective of this study was to determine the effect of intravenous (i.v.) flumazenil on midazolam apparent oral clearance (a surrogate marker of CYP3A activity). Midazolam pharmacodynamics were also evaluated. This was a randomized, double-blind, placebo-controlled, single-dose, two-way crossover study. 16 healthy volunteers (8 women) were concomitantly administered i.v. flumazenil 0.005 mg/kg or i.v. placebo and oral midazolam 0.075 mg/kg. Blood samples were obtained to determine midazolam and flumazenil plasma concentrations. Bioequivalence was assessed by determining geometric mean ratios (GMR) and 90% confidence intervals (90% CI). Baseline and post dose digit symbol substitution tests (DSST), Groton maze learning tests (GMLT), and Stanford sleepiness scales (SSS) were conducted. Apparent oral clearance was 2,030 +/- 651 and 1,939 +/- 658 ml/min for the midazolam plus flumazenil and midazolam plus placebo groups. Equivalence in midazolam apparent oral clearance was observed (%GMR flumazenil/placebo, 90% CI 104.8, 94 - 116.6%). Flumazenil partially attenuated oral midazolam pharmacodynamics. Exploratory post hoc analyses revealed that midazolam exposure was 1.9-fold higher in men compared to women. i.v. flumazenil can be used in conjunction with oral midazolam for CYP3A phenotyping.

CAN CONTINUING EDUCATION EVER BE HARMFUL?

CAN CONTINUING EDUCATION EVER BE HARMFUL?

Fast cardiologist-administered midazolam for electrical cardioversion of atrial fibrillation

To evaluate the safety and the feasibility of sedation administered by cardiologists with rapid intravenous bolus of midazolam followed by flumazenil infusion during transthoracic biphasic electrical cardioversion (TEC) for atrial fibrillation (AF). Two hundred and sixty-five consecutive patients (119 females, mean age 67.4 +/- 8.5 years) with either acute (24 patients) or persistent AF (mean arrhythmia duration 3.7 +/- 3.0 months) underwent TEC. Midazolam (0.05 mg/kg) was administered as rapid intravenous bolus by the cardiologist, whereas the anaesthesiologist was simply alerted. At the end of the procedure, intravenous flumazenil 0.25 mg was given, followed by 0.25 mg over 1 h. Patients received continuous electrocardiographic and pulse-oxymetric monitoring. Adequate sedation was obtained in 262 patients (98.9%), with a mean midazolam dose of 4.4 +/- 0.9 mg. After drug administration, the mean time to patient's sedation and reawakening were 3.1 +/- 1.9 and 6.1 +/- 2.7 min, respectively. The mean reduction in oxygen saturation was 5.4 +/- 3.7%. Sinus rhythm was restored in 254 patients (95.8%). All but 41 patients (15.5%) were completely amnesic. None reported pain. No adverse events were registered. No urgent call for the anaesthesiologist was made. Conscious sedation with fast-administered midazolam followed by flumazenil for cardioversion of atrial fibrillation is safe, effective and well tolerated, easing the procedure and shortening its duration.

Effects of γ-Aminobutyric Acid–Modulating Drugs on Working Memory and Brain Function in Patients With Schizophrenia

Cognitive impairment causes morbidity in schizophrenia and could be due to abnormalities of cortical interneurons using the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). To test the predictions that cognitive and brain functional responses to GABA-modulating drugs are correlated and abnormal in schizophrenia. Pharmacological functional magnetic resonance imaging study of 2 groups, each undergoing scanning 3 times, using an N-back working memory task, after placebo, lorazepam, or flumazenil administration. Eleven patients with chronic schizophrenia were recruited from a rehabilitation service, and 11 healthy volunteers matched for age, sex, and premorbid IQ were recruited from the local community. Intervention Participants received 2 mg of oral lorazepam, a 0.9-mg intravenous flumazenil bolus followed by a flumazenil infusion of 0.0102 mg/min, or oral and intravenous placebo. Working memory performance was summarized by the target discrimination index at several levels of difficulty. Increasing (or decreasing) brain functional activation in response to increasing task difficulty was summarized by the positive (or negative) load response. Lorazepam impaired performance and flumazenil enhanced it; these cognitive effects were more salient in schizophrenic patients. Functional magnetic resonance imaging demonstrated positive load response in a frontoparietal system and negative load response in the temporal and posterior cingulate regions; activation of the frontoparietal cortex was positively correlated with deactivation of the temporocingulate cortex. After placebo administration, schizophrenic patients had abnormally attenuated activation of the frontoparietal cortex and deactivation of the temporocingulate cortex; this pattern was mimicked in healthy volunteers and exacerbated in schizophrenic patients by lorazepam. However, in schizophrenic patients, flumazenil enhanced deactivation of the temporocingulate and activation of the anterior cingulate cortices. The GABA-modulating drugs differentially affect working memory performance and brain function in schizophrenia. Cognitive impairment in schizophrenia may reflect abnormal inhibitory function and could be treated by drugs targeting GABA neurotransmission.

Intravenous flumazenil in Parkinson's disease

Intravenous flumazenil in Parkinson's disease

Intravenous flumazenil for Parkinson's disease: A single dose, double blind, placebo controlled, cross‐over trial

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.

Individual differences in aggressive responding to intravenous flumazenil administration in adult male parolees

Nonhuman and human studies have shown that benzodiazepine (BZD) receptor agonists can modify aggressive behaviour. However, it is unknown whether flumazenil, a BZD receptor antagonist, enhances or inhibits aggressive behaviour. The present study was designed to investigate the effects of acute administrations of flumazenil on aggressive responding in adult humans. Six adult males with histories of childhood conduct disorder (DSM IV R) participated in experimental sessions. Aggression was measured using the Point Subtraction Aggression Paradigm (PSAP; Cherek 1992), which provided subjects with aggressive and monetary-reinforced response options. Acute doses of flumazenil (2 and 3mg) did not produce statistically significant changes in either monetary-reinforced responding or aggressive responding. The analysis of individual subjects data revealed that aggressive responses varied across subjects. The results are discussed in terms of individual differences based on the previous history of BZD abuse. Additional laboratory research is needed to better clarify the behavioural mechanisms by which BZD receptor antagonists modify human aggressive responding.

Oral triazolam sedation in implant dentistry.

Triazolam can be helpful for sedating dental implant patients when administered orally or sublingually in low dosages of 0.125 or 0.25 mg, but not exceeding 0.5 mg. It is a fast- but short-acting benzodiazepine with few side effects, and it has a long record of successful use. Its effects can be reversed with incremental intravenous flumazenil, although there is a risk of seizure. Triazolam has not been shown to be carcinogenic, and it has a low potential for abuse and addiction. It is contraindicated in patients who are pregnant, breast-feeding, and those concomitantly taking ethanol, macrolid antibiotics, some protease inhibitors, psychotropic medications, ketoconazole, itraconazole, nefaxodone, or other medications that impair oxidative metabolism mediated by cytochrome P450 3A (CYP 3A). Triazolam should be used with caution in patients taking grapefruit juice, cyclosporine, and other drugs such as calcium channel blockers including nifedipine, verapamil, and diltiazem. The lowest effective dose should be used.

Pharmacokinetics (PK) and pharmacodynamics (PD) of orally (PO) administered midazolam (MDZ) in the presence and absence of intravenous (IV) flumazenil (F) in healthy volunteers

Clinical Pharmacology &amp; Therapeutics (2003) 73, P15–P15; doi:

Short-term effects of intravenous benzodiazepines on autonomic neurocardiac regulation in humans: A comparison between midazolam, diazepam, and lorazepam

To evaluate the effects of intravenously applied diazepam, lorazepam, and midazolam on autonomic neurocardiac regulation assessed by standardized measurements of heart rate variability. Prospective, randomized clinical study. University teaching hospital. Forty-five patients, who underwent a gastroscopy, were randomly assigned to intravenous premedication with midazolam (5 mg), diazepam (10 mg), or lorazepam (4 mg). Six subjects refused an injection and served as nonpremedicated controls. Serial recordings of the 5-min resting heart rate variability were obtained before and 15 and 30 mins after premedication. Seven benzodiazepine-treated patients received intravenous flumazenil (0.5 mg). The average doses applied were 0.07 mg/kg for midazolam, 0.13 mg/kg for diazepam, and 0.06 mg/kg for lorazepam. Fifteen minutes after intravenous benzodiazepines were administered, we found an increase in resting heart rate and a reduction of vagal tone compared with baseline in all three benzodiazepine-treated subgroups. Multivariate analysis (covariate age) of the changes in heart rate variability indices over the experimental course revealed a significant reduction in absolute high-frequency power with midazolam or diazepam compared with nonpremedicated subjects. Moreover, midazolam-treated subjects showed a significantly larger reduction in relative high-frequency power not only compared with nontreated subjects, but also compared with lorazepam- or diazepam-treated subjects. Vagal tone remained reduced compared with baseline even 30 mins after benzodiazepine application, however, the resting heart rate decreased toward baseline levels. After flumazenil administration, there was a linear correlation between an increase in high-frequency power and a corresponding decrease in resting heart rate. Benzodiazepines can influence autonomic neurocardiac regulation in man, probably through their interaction with the gamma-aminobutyric acidA-receptor chloride ion channel complex. The pattern of findings suggests that intravenous midazolam, diazepam, and lorazepam influence human autonomic neurocardiac regulation in a biphasic way. First, they cause a reduction of central vagal tone, and second, they may decrease the cardiac pacemaker directly. Flumazenil completely abolished the autonomic neurocardiac regulation effects of benzodiazepines.

A randomised crossover trial of post-operative cognitive and psychomotor recovery from benzodiazepine sedation: effects of reversal with flumazenil over a prolonged recovery period

Objective: To study the post-operative cognitive and psychomotor recovery from midazolam conscious sedation, after reversal with the benzodiazepine antagonist flumazenil over a prolonged recovery period.Design: A prospective, double-blind, randomised, crossover trial.Setting: Out-patient Sedation Department, Newcastle Dental Hospital and SchoolMethod: Eighteen patients, ASA I or II, received midazolam on two separate occasions to undergo equivalent dental treatment. Following treatment patients were reversed with intravenous flumazenil or saline (placebo) at alternate appointments. Assessment of mood and cognitive function was undertaken using a highly sensitive and specific computerised battery of cognitive tests administered by telephone. Cognitive and psychomotor tests were administered prior to sedation and every hour for 6 hours post reversal.Results: Results indicated no significant effect of flumazenil on simple reaction time and choice reaction time but did show a trend of reversing the effects of midazolam on numeric working memory and word recognition.Conclusion: The cognitive and psychomotor effects of the sedation were not fully reversed by flumazenil. Cognitive impairments were still present up to 6 hours post-reversal, despite patients appearing clinically more alert. This has important implications for treatment protocols and discharge instructions.

Sedation reversal with flumazenil?

Objective To study the post-operative cognitive and psychomotor recovery from midazolam conscious sedation, after reversal with the benzodiazepine antagonist flumazenil over a prolonged recovery period. Design A prospective, double-blind, randomised, crossover trial. Setting Out-patient Sedation Department, Newcastle Dental Hospital and School Method Eighteen patients, ASA I or II, received midazolam on two separate occasions to undergo equivalent dental treatment. Following treatment patients were reversed with intravenous flumazenil or saline (placebo) at alternate appointments. Assessment of mood and cognitive function was undertaken using a highly sensitive and specific computerised battery of cognitive tests administered by telephone. Cognitive and psychomotor tests were administered prior to sedation and every hour for 6 hours post reversal. Results Results indicated no significant effect of flumazenil on simple reaction time and choice reaction time but did show a trend of reversing the effects of midazolam on numeric working memory and word recognition. Conclusion The cognitive and psychomotor effects of the sedation were not fully reversed by flumazenil. Cognitive impairments were still present up to 6 hours post-reversal, despite patients appearing clinically more alert. This has important implications for treatment protocols and discharge instructions.

A randomised crossover trial of post-operative cognitive and psychomotor recovery from benzodiazepine sedation: effects of reversal with flumazenil over a prolonged recovery period

To study the post-operative cognitive and psychomotor recovery from midazolam conscious sedation, after reversal with the benzodiazepine antagonist flumazenil over a prolonged recovery period. A prospective, double-blind, randomised, crossover trial. Out-patient Sedation Department, Newcastle Dental Hospital and School Eighteen patients, ASA I or II, received midazolam on two separate occasions to undergo equivalent dental treatment. Following treatment patients were reversed with intravenous flumazenil or saline (placebo) at alternate appointments. Assessment of mood and cognitive function was undertaken using a highly sensitive and specific computerised battery of cognitive tests administered by telephone. Cognitive and psychomotor tests were administered prior to sedation and every hour for 6 hours post reversal. Results indicated no significant effect of flumazenil on simple reaction time and choice reaction time but did show a trend of reversing the effects of midazolam on numeric working memory and word recognition. The cognitive and psychomotor effects of the sedation were not fully reversed by flumazenil. Cognitive impairments were still present up to 6 hours post-reversal, despite patients appearing clinically more alert. This has important implications for treatment protocols and discharge instructions.

A double-blind, placebo-controlled single dose trial of intravenous flumazenil in Alzheimer's disease

Benzodiazepine agonists have been shown to reduce cognitive functioning by producing attentional deficits similar to those produced by muscarinic antagonists. It has therefore been postulated that benzodiazepine antagonists may improve cognitive function in patients with Alzheimer's disease by indirectly increasing cholinergic function. Eleven patients with mild to moderate Alzheimer's disease took part in a double-blind placebo-controlled crossover study of the effects of a single 1 mg injection of the benzodiazepine antagonist flumazenil on cognitive function. Validated computer tests were used to assess change in cognitive function over time after each injection. No adverse effects of the drug were experienced. Speed on both a simple reaction time task and a picture recognition task was significantly slowed by flumazenil compared to placebo at 15 min (p=0.027 and p=0.01). Accuracy of recalling pictures was significantly reduced compared to baseline (p=0.0002), but this was not statistically significant when compared to placebo. Possible reasons for these findings are discussed and it is concluded that a single injection of 1 mg flumazenil produces cognitive slowing in patients with Alzheimer's disease. It is suggested that further research is needed into central benzodiazepine receptor density and function, as well as dose–response studies using flumazenil. Copyright © 1999 John Wiley & Sons, Ltd.