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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.

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.)

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.

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.

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.

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.

Objective: The goal of this study was to test the effect of concomitant administration of flumazenil (FL) and morphine (MO) on immediate postoperative analgesia and the MO requirement to control pain in human beings., Design and Interventions: Thirty-six patients undergoing inguinal hernioplasty under lidocaine epidural anesthesia were enrolled in this double-blind, randomized, controlled study. On the first complaint of pain, either MO (2 mg) only or MO (2 mg) plus FL (0.2 mg) was administered. Additional doses of the same medications administered via a patient-controlled analgesia device with a 10-minute lockout period were available thereafter. The study continued for 2 hours after the loading doses of the medications were administered, with an additional 2-hour period of observation., Results: Thirty-two patients completed the study. Both groups reached a similar satisfactory equianalgesic state (2 in a 0-10 visual analogue scale). The MO plus FL group consumed 9.5 +/- 1.1 mg of MO versus 14.1 +/- 1.1 mg of MO (p < 0.001) in the MO only group. The MO plus FL patients were subjectively (visual analogue scale) more comfortable and less sedated than the MO patients. "Fine" coordination (using an electronic maze) and "coarse" coordination (measured by transferring a pen from one hand to another as rapidly as possible with both arms placed inside an 80-cm metal frame) in the MO group were worse than in the MO plus FL group. End-tidal CO2 increased and blood pressure decreased in the MO group. There were few and insignificant side effects in the MO group. None of these patients required an MO antagonist, and recovery was prolonged in none., Conclusions: Flumazenil afforded lower MO consumption during the immediate postoperative period. Cognitive, hemodynamic, and respiratory functions were better after MO plus FL than after MO alone.

Objectives: To evaluate the cardiovascular response and acute stress reaction after arousal induced by a benzodiazepine antagonist, flumazenil, in patients sedated with midazolam., Design: Prospective study., Setting: Emergency center in a university hospital., Patients: A total of 12 patients were ventilated mechanically under sedation with midazolam., Interventions: We monitored the consciousness level, heart rate, systemic blood pressure, pulmonary artery pressure, and pulmonary artery occlusion pressure before and after a bolus injection of 0.5 mg of flumazenil. The score for the consciousness level represents the sum of the scores for eye opening and best motor response, as determined by the Glasgow Coma Scale. We measured the cardiac output, concentrations of norepinephrine, epinephrine, and 3-methoxy-4-hydroxyphenylethyleneglycol in plasma, and concentration of cortisol in serum. We calculated the left ventricular ejection fraction, cardiac index, systemic vascular resistance index, pressure-rate product, systemic oxygen delivery, and systemic oxygen consumption at 0, 10, 30, and 60 mins after injection of flumazenil., Measurements and Main Results: The serum benzodiazepine's receptor binding activity in serum was in the range from 50 to 1000 ng/mL before injection of flumazenil. Flumazenil improved the consciousness level from 6.7+/-2.0 to 8.9+/-1.6 and induced transient elevations in heart rate, blood pressure, systolic pulmonary artery pressure, and pulmonary artery occlusion pressure. Left ventricular ejection fraction, oxygen delivery index, and pressure-rate product increased significantly, from 61%+/-8%, 640+/-170 mL/min/m2, and 13,300+/-2600 mm Hg/min at 0 mins to 67% +/-5%, 710+/-220 mL/min/m2, and 16,500+/-4400 mm Hg/min at 10 mins, respectively. Concentrations of norepinephrine and epinephrine in plasma increased significantly, from 890+/-840 pg/mL and 220+/-360 pg/mL, respectively, at 0 mins to 990+/-850 pg/mL and 270+/-300 pg/mL, respectively, at 10 mins. There were no significant changes in the plasma concentration of 3-methoxy-4-hydroxyphenylethyleneglycol, the serum concentration of cortisol after the administration of flumazenil., Conclusions: Flumazenil did not result in a significant acute stress reaction in midazolam-sedated patients, but it increased myocardial oxygen consumption by enhancing sympathetic nervous activity or antagonizing cardiovascular depression induced by midazolam.

Background: Flumazenil is a benzodiazepine receptor antagonist thought to be panicogenic in patients with panic disorder but not in control subjects. The present study was undertaken to compare the effects of flumazenil in patients with panic disorder and those in healthy control subjects, and also to determine whether panic disorder is characterized by a hypothesized shift in the benzodiazepine receptor "set-point" and a differential response to flumazenil., Methods: Eight patients with panic disorder and 8 matched control subjects were given infusions of saline and flumazenil in randomized order. Psychopathological changes, cardiovascular parameters, together with adrenocorticotropic hormone (ACTH) and cortisol secretion were recorded., Results: Patient and control subjects responded to flumazenil uniformly; there was no evidence for an anxiogenic activity of flumazenil in control subjects or panic disorder patients. ACTH and cortisol levels were also not differentially influenced by flumazenil or panic disorder diagnosis. Heart rate and systolic blood pressure in both groups were slightly but significantly reduced by flumazenil compared to saline., Conclusions: These findings do not support the view that panic disorder patients and control subjects respond differentially to flumazenil or that the suggested shift in the benzodiazepine receptor "set-point," which leads to an inverse agonistic activity of flumazenil, characterizes panic disorder.

The rationale for use of benzodiazepine receptor antagonists is based on the so-called benzodiazepine pathogenetic hypothesis of hepatic encephalopathy (HE). To assess the efficacy of flumazenil, a specific benzodiazepine receptor antagonist, in a large and selected population of cirrhotic patients with severe HE, we conducted a double-blind, placebo-controlled, cross-over trial on 527 cirrhotic patients with HE grade III and IVa admitted to Intensive Care Units over a 5-year period; among them, 265 (132 of grade III and 133 of grade IVa) received flumazenil, whereas 262 (130 of grade III and 132 of grade IVa) received placebo. Treatment was begun within 15 minutes of randomization; the response to treatment was assessed by neurological score and by continuous electroencephalographic (EEG) recordings. Improvement of the neurological score was documented in 17.5% of grade III patients treated with flumazenil and in 14.7% of grade IVa patients, compared, respectively, with 3.8% and 2.7% of the patients of both groups treated with placebo. Improvements in EEG tracings were observed in 27.8% of grade III patients and in 21.5% of grade IVa patients, compared, respectively, with 5% and 3.3% of the patients of both groups treated with placebo. Benzodiazepines were detected in the serum of 10 patients (4 in grade III group and 6 in grade IVa group). Flumazenil is beneficial only in a selected subset of cirrhotic patients with severe HE; the applicability of this treatment to unselected patients with severe HE still remains to be determined.

Many patients who receive electroconvulsive therapy (ECT) are benzodiazepine dependent or are anxious and require benzodiazepine drugs. Because these agents may diminish the therapeutic effectiveness of ECT, we explored the dosing, safety, and efficacy of pre-ECT flumazenil administration, a benzodiazepine-competitive antagonist, in patients receiving benzodiazepine medications. We report our experience with 35 patients who received both flumazenil and benzodiazepine drugs during their ECT course. We compared seizure duration with and without flumazenil and compared treatment efficacy to 49 patients who received ECT without either of these medications. Flumazenil could be safely administered with ECT. A few subjects taking higher chronic benzodiazepine dosages experienced breakthrough anxiety or withdrawal symptoms, which were well managed by dosing flumazenil immediately before the anesthetic agent and by immediate posttreatment benzodiazepine administration. A dose of 0.4-0.5 mg was adequate for all but those taking the highest benzodiazepine dosages, where 0.8-1.0 mg resulted in a clinically more effective reversal. No differences in efficacy or seizure duration were found as a function of flumazenil administration. Flumazenil offers the promise of safe and effective ECT in patients receiving benzodiazepine drugs. Follow-up outcome investigation on a random assignment basis will be necessary for definitive assessment of the value of flumazenil. In addition, the direct effect of benzodiazepine drugs and the flumazenil/benzodiazepine combination on ECT seizures remains to be determined.

The purpose of this study was to determine if flumazenil is absorbed from broncho-pulmonary tissue after intratracheal administration and whether therapeutically significant plasma concentrations can be obtained. Six elective surgical patients received a dose of 1.0 mg flumazenil in 10 mL saline intratracheally during general anesthesia. Blood samples were drawn for 6 hours after administration and plasma concentrations were determined by gas chromatography-mass spectrometry (GC-MS). An average peak plasma flumazenil concentration of 65.9 +/- 43.1 ng/mL was attained within 1 minute after administration. No patients reported chest discomfort or dyspnea upon awakening and there were no other side effects noted. Administration of flumazenil via an endotracheal tube results in rapid attainment of therapeutic blood levels.

The worldwide expansion in the use of benzodiazepines has led to their frequent, and often inappropriate, use and to increase in their involvement in self-induced poisoning and iatrogenic overdosing. Flumazenil is a specific and competitive antagonist at the central benzodiazepine receptor, reversing all effects of benzodiazepine agonists without tranquillising or anticonvulsant actions. Incremental intravenous bolus injections of flumazenil 0.1 to 0.3 mg are the most effective and well tolerated in the diagnosis and treatment of pure benzodiazepine overdose; additional boluses or an infusion (0.3 to 0.5 mg/h) can be given to prevent patients from relapsing into coma. Intravenous flumazenil 10 to 20 micrograms/kg is effective in neonates and small children. Intramuscular, oral (20 to 25 mg 3 times daily or as required) and rectal administration may be used as alternatives in long term regimens. Patients with mixed-drug overdose require higher doses (up to 2 mg bolus, approximately equal to 1 mg/h infusion) to regain consciousness. Children and the elderly, chronically ill patients, and pregnant women and their fetuses all respond satisfactorily to flumazenil, but the usefulness of the drug in patients with hepatic encephalopathy and alcohol overdose is debatable. The use of flumazenil results in complete awakening with restoration of upper airway protective reflexes, thus enabling gastric lavage to be performed and transfer of the patient from the emergency room to another hospital department. Resumption of effective spontaneous respiration allows for expeditious extubation, weaning off mechanical ventilation or the avoidance of endotracheal intubation. While flumazenil is not associated with haemodynamic adverse effects, caution should be exercised when using this agent in patients who have co-ingested chloral hydrate to carbamazepine or whose ECG shows abnormalities typical to those seen after overdose with tricyclic antidepressants (TCAs); the use of flumazenil in the presence of these drugs can sometimes induce treatable cardiac dysrrhythmia. Flumazenil per se does not induce adverse effects. Coma reversal by flumazenil may cause mild, short-lived reactions caused by sudden awakening. Withdrawal symptoms in long term benzodiazepine users and seizures in patients who have taken an overdose of TCA or carbamazepine and a benzodiazepine can occur with flumazenil; these symptoms are avoidable by utilising slow flumazenil dose titration.

We studied the timing and side effects of flumazenil treatment for 10 healthy volunteers and 46 dental outpatients who received intravenous sedation with midazolam. For the volunteers, vital signs were monitored before and after intravenous injection of midazolam and flumazenil. In addition, grip strength, signs and symptoms, and performance on the Romberg's test and addition tests were evaluated 30 min and 60 min after midazolam injection as well as after flumazenil injection. There were no significant changes in vital signs before, immediately after, or 50 min after injection of flumazenil, the latter time corresponding to the half-life of the drug. Thus, awakening from sedation was associated with no effects on the cardiovascular or respiratory systems. Distinct effects of flumazenil were demonstrated by the Romberg's test and the assessment of sedation status. Flumazenil had no effect on the outcome of the addition test. For the outpatients, sedation status and signs and symptoms were studied in patients undergoing procedures lasting 30 min or less (group S) and those undergoing procedures lasting 31 to 60 min (group L). Three patients in group S and one in group L had signs and symptoms of resedation. After treatment with flumazenil, abnormalities such as excitability and nausea were reported by only two patients in group L. One patient in group S had drowsiness that did not resolve after injection of flumazenil and continued until the following day. Our results indicate that flumazenil should be given at least 60 min after intravenous sedation with midazolam in dental outpatients. Moreover, caution should be exercised with regard to the potential side effects of flumazenil.

Study Objective: To determine the effects of midazolam and its antagonism with flumazenil on psychomotor function as assessed by the perceptive accuracy test (PAT) and choice reaction time (CRT)., Design: Double-blind, cross-over, randomized, placebo-controlled study., Setting: Department of Anaesthesiology, University Hospital, Linköping, Sweden., Subjects: 11 healthy volunteers (6 females, 5 males, mean age 32 years)., Interventions: Midazolam 0.1 mg/kg (Group MH), midazolam 0.035 mg/kg (Group ML), or placebo (Group PL) were injected intravenously (IV) in a cross-over design. Flumazenil 0.5 mg was injected after 60 minutes. Plasma concentrations of midazolam were measured at 3, 30, 60 and 75 minutes., Measurements and Main Results: Baseline values were first obtained on psychomotor tests including the PAT and CRT. These tests were then repeated 30 and 60 minutes after the IV injection of midazolam or placebo, and repeated 15 and 30 minutes following the injection of flumazenil. A dose-dependent effect of midazolam was seen on the PAT and CRT. Flumazenil completely reversed the psychomotor effects of midazolam in Group ML at 60 minutes but not in Group MH, and this action was clearly detected by the PAT. Psychomotor tests had returned to baseline values when the plasma concentration of midazolam was below 33 ng/ml. A marked inter-individual variation was seen on the PAT, CRT, and in the correlation between the plasma concentration and the results on the PAT., Conclusions: There was a dose-dependent deterioration in psychomotor performance in subjects given midazolam. The PAT was sensitive in the detection of these residual effects, but a large inter-individual variation in the psychomotor effects of midazolam was evident that could be due to pharmacodynamic and pharmacokinetic variability between individuals. Flumazenil in a dose of 0.5 mg IV completely reversed the effects of low-dose, but not high-dose, midazolam.

A 52-year-old female patient who was medicated chronically with sodium valproate, an anticonvulsant drug, underwent spino-peritoneal shunt operation. Firstly, spinal drain was placed under local anesthesia and with intravenous diazepam, which was antagonized by flumazenil, a specific benzodiazepine receptor antagonist, without adverse effect. Secondly, peritoneal drain was placed and shunt operation was completed under general anesthesia. After the operation flumazenil was administered again in order to accelerate anesthesia recovery. Just after the second flumazenil administration she developed generalised convulsion and coma. Convulsion disappeared immediately and full consciousness was restored several hours after the attack. We have discussed the possible mechanism of the flumazenil-induced convulsion.

Flumazenil is a specific benzodiazepine antagonist. It competitively inhibits the action of benzodiazepines at gamma aminobutyric acid (GABA) receptors in the central nervous system and thus reverses the sedative effects of benzodiazepines. Usually, it is given intravenously as a bolus dose or as an infusion. It has a short duration of action. Flumazenil is extensively metabolized to compounds that have minimal benzodiazepine antagonistic properties. Reversal of sedation can be useful in many conditions that are often encountered in the critically ill. The adverse effects of its use are usually predictable and, with sufficient clinical monitoring, are usually avoidable. These properties make it a useful and safe drug when used appropriately.