Reversal of sedation by prolonged infusion of flumazenil (Anexate, Ro 15–1788)

A 22-year-old male was involved in a road traffic accident and sustained multiple injuries. He received an infusion of midazolam to sedate him during a period of artificial ventilation. His conscious level remained depressed 36 hours after the infusion was discontinued but the sedation was completely reversed with flumazenil. An infusion was started because of the short duration of action of flumazenil, and continued for 8 days. The infusion was stopped seven times during this period and on each occasion except the last, his conscious level deteriorated but returned to normal when flumazenil was administered again. Plasma concentrations of midazolam and alpha-hydroxymidazolam were measured and found to be low during this period. Possible explanations for this finding are discussed.     

Cardiovascular responses to flumazenil-induced arousal after arterial surgery

Patients who underwent peripheral arterial surgery had anaesthesia maintained with an infusion of midazolam. They were allowed either to recover spontaneously or to have the effects of midazolam reversed by flumazenil at the end of surgery. This study demonstrated that the cardiovascular responses to arousal using flumazenil are no different from those seen when the patient is allowed to recover in the normal way. This result has obvious advantages for clinical practice but the dangers of resedation must not be forgotten.     

Reversal of prolonged sedation using flumazenil in critically ill patients

Thirteen critically ill patients received flumazenil after multiple doses, or an infusion, of midazolam was used as part of a sedation regimen to facilitate intensive care. All patients remained excessively sedated after the midazolam was stopped for 6 hours or longer. An improvement in conscious level occurred in eight patients (61%). In four of these eight patients, the duration of action of flumazenil necessitated its continued administration by an infusion to maintain the improvement in conscious level. The dose of flumazenil required each hour was less than estimated previously; this indicates that it may be subjected to similar alterations of elimination as those described for midazolam. Flumazenil appears to be a useful drug for the reversal of prolonged benzodiazepine sedation but repeated bolus doses or an infusion are needed if significant accumulation of benzodiazepines has occurred.     

Midazolam and flumazenil in gastroenterologys

Flumazenil, a specific benzodiazepine antagonist, has been used to reverse sedation in a double-blind, controlled study of patients undergoing upper gastrointestinal (GI) endoscopy. Forty patients in each of two centres were given a standard dose of either flumazenil (n = 40) or placebo (n = 40) after gastroscopy under midazolam sedation. Assessments were made of degree of sedation, psychomotor ability and amnesia up to 24 h after endoscopy. In patients treated with flumazenil, sedation was effectively reversed within 5 min in 77.5% of cases compared to 27.5% of patients treated with placebo. The difference was both clinically and statistically significant at 5 and 30 min but not at 60 min after reversal. There was no evidence of resedation 18 to 24 h later. Times to complete Trieger dot-joining tests were significantly faster in the flumazenil group at 5, 30 and 60 min. Amnesia for the procedure was retained but did not occur for events after administration of flumazenil. The only adverse event was severe pain in the arm of one patient during the injection of flumazenil. Flumazenil rapidly and safely reverses midazolam-induced sedation while retaining amnesia for gastroscopy.     

Residual psychomotor effects following reversal of midazolam sedation with flumazenil

The ability of flumazenil to reverse the effects of midazolam sedation was examined in a randomised, crossover, placebo controlled study in six male volunteers. Subjects received intravenous injections of either (a) midazolam 10 mg followed 10 minutes later by flumazenil 1.0 mg or (b) midazolam 10 mg followed after 10 minutes by flumazenil 4 mg or (c) placebo followed after 10 minutes by placebo. Post reversal drug effects were examined using a psychomotor battery (critical flicker fusion, digit symbol substitution, tapping test, ball-bearing test, number recall, reflex time) and linear analogue mood scales. It was found that a residual psychomotor deficit was present following flumazenil and that this persisted for up to 125 minutes after the 1.0 mg dose and 65 minutes following 4 mg. A small deterioration in performance was apparent after initial reversal with 1.0 mg, the peak deterioration occurring at 35 minutes.     

A randomised,controlled trial of cognitive and psychomotor recovery from midazolam sedation following reversal with oral flumazenil

Flumazenil is traditionally administered intravenously to reverse the adverse effects of over sedation with benzodiazepines. The aim of this study was to test postoperative cognitive and psychomotor recovery from midazolam conscious sedation, following reversal with orally administered flumazenil. It was hypothesised that when administered by the oral route, flumazenil may enhance recovery over a prolonged period, thus increasing safety. Eighteen patients requiring intravenous midazolam sedation for dental treatment completed a randomised, double-blind, crossover trial. Following treatment the patients' sedation was reversed using either flumazenil or saline (as placebo), administered orally, on alternate appointments. Assessment of mood and cognitive function were undertaken using ClinPhone.cdr(R), a highly sensitive and specific computerised battery of cognitive tests administered by telephone prior to sedation and every hour for seven hours post reversal. Results indicate that within 20 min of administration, oral flumazenil is capable of partially reversing some cognitive and psychomotor impairments but the attentional and stimulus discrimination effects of midazolam sedation still remain.     

Sedative and ventilatory effects of midazolam infusion: effect of flumazenil reversal

The purpose of this study was to evaluate the effects of flumazenil (1 mg iv) on the ventilatory response of premedicated patients receiving a continuous infusion of midazolam for sedation. After assessing baseline ventilatory function using a modified Read rebreathing method for determining hypercapnic ventilatory drive, 16 healthy outpatients were administered fentanyl, 50 μg iv, and midazolam 2 mg iv followed by a variable-rate midazolam infusion, 0.3–0.5 mg · min^?1. Upon termination of the midazolam infusion, serum midazolam concentrations were measured and ventilatory function was reassessed. Then, 10 ml of either saline or flumazenil (1 mg) were administered according to a randomized, double-blind protocol. Ventilatory function was subsequently measured at 5 min, 30 min and 60 min intervals after study drug. Compared with the baseline value, midazolam infusion reduced tidal volume and increased respiratory rate and alveolar dead space. However, midazolam did not decrease the slope of the CO₂-response curve. Flumazenil reduced the degree of midazolam-induced sedation and the decrease in tidal volume (P < 0.05), but not the change in resting respiratory rate. In some patients, the ventilatory response to hypercarbia actually decreased after flumazenil administration compared with the immediate prereversal (sedated) values. It is concluded that midazolam infusion, 0.43 mg · min^?1, did not impair CO₂-responsiveness. Flumazenil’s effect on central ventilatory drive was more variable than its reversal of midazolam-induced sedation.     

Sedation with intravenous midazolam during upper gastrointestinal endoscopy--changes in hemodynamics, oxygen saturation and memory

BACKGROUND: Cardiorespiratory adverse effects are often observed in patients undergoing upper gastrointestinal endoscopy with sedation. In this study, we examined hemodynamics, oxygen saturation and memory during upper gastrointestinal endoscopy under sedation with intravenous midazolam. METHODS: Eight healthy outpatients without any obvious complications received intravenous midazolam 5 mg for sedation for upper gastrointestinal endoscopy. Blood pressure, heart rate and percutaneous arterial oxygen saturation (SpO2) were measured before, during and after endoscopy. After the arousal by intravenous flumazenil, we inquired the patients about the level of memory during the endoscopy. RESULTS: Blood pressure decreased significantly two minutes after midazolam administration, but increased significantly after the insertion of an endoscope which was not different from the control value. Heart rate increased significantly one and three minutes after the insertion of the endoscope. SpO2 decreased significantly after midazolam administration and stayed at around 95%. No patients remembered the procedure. CONCLUSIONS: Sedation with intravenous midazolam during upper gastrointestinal endoscopy is useful to control the cardiovascular responses, and to obtain amnesia. However, a decrease in SpO2 should be watched carefully.     

Ro 15-1788 for postoperative recovery

In a double-blind randomised study, 100 women who underwent induced abortion under midazolam anaesthesia were given the benzodiazepine antagonist Ro 15-1788 or placebo after termination of anaesthesia. Recovery was assessed by means of a modified Steward coma scale. Following incremental doses of Ro 15-1788, 56% of the patients were fully awake within 3 minutes and 92% after 5 minutes, which was significant compared to the placebo group. The median duration of amnesia was 91 minutes after Ro 15-1788 compared to 121 minutes in the placebo group (p less than 0.001). The median dose of Ro 15-1788 was 0.4 mg. A slight positive correlation between total dose of Ro 15-1788 and total amount of midazolam was found. Nausea and/or vomiting were found to be more frequent in the Ro 15-1788 group, but otherwise we found no differences between groups with regard to either side effects or cardiorespiratory function. Ro 15-1788 is evidently an effective antagonist to the sedation induced by midazolam.     

Timing and side effects of flumazenil for dental outpatients receiving intravenous sedation with midazolam.

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.     

Antagonism of midazolam sedation by flumazenil: a placebo-controlled study in patients recovering from intravenous anaesthesia with high doses of midazolam

Twenty adult surgical patients were anaesthetized with high-dose midazolam and alfentanil by infusion, vecuronium, and intubated and ventilated with 50% N2O in O2. The midazolam and alfentanil infusions were stopped at the end of surgery. Residual neuromuscular blockade and ventilatory depression were antagonized and the patients extubated. In the recovery room, patients were randomly allocated to receive either flumazenil 1 mg of placebo i.v. Before, and until 2 h after injection, patients were asked to perform psychomotor tests. In addition, sedation, comprehension and orientation were scored. The flumazenil (n = 10) and the placebo (n = 10) groups were comparable. Prior to injection all patients were heavily sedated. After flumazenil all were awake within 2-3 min, but fell asleep again 15-60 min later. The improvement in test scores was sustained for a longer time. After placebo, patients awoke in 1-2 h. At 60 and 120 min, test scores in the two groups were similar. Heart rate, blood pressure and respiration rate did not change. No side-effects were observed or reported. It is concluded that flumazenil is an effective and safe antagonist of high dose midazolam, with a rapid onset but a short duration of action.     

MIDAZOLAM AND FLUMAZENIL IN THE ANAESTHETIC MANAGEMENT OF TRIGEMINAL NERVE THERMOCOAGULATION

A technique is described for the anaesthetic management of trigeminalnerve thermocoagulation by administration of repeated dosesof midazolam and flumazenil. "Wake-up" times after administrationof flumazenil in 20 patients were shorter than those reportedduring spontaneous recovery from methohexitone or propofol anaesthesia.The midazolam dose required for a second phase of sedation afterantagonism of the first with flumazenil was significantly lessthan that for the first phase of sedation. There was no evidenceof postoperative resedation. Reversal of sedation was associatedwith an increase in arterial pressure.     

Use of flumazenil for intraoperative arousal during spine fusion.

The intraoperative arousal test is used to detect potential damage to the spinal cord during spine fusion. We determined whether a continuous midazolam infusion, the effects of which are antagonized by flumazenil when the arousal test is needed, is associated with good control of the timing of arousal and with no adverse reactions. In a randomized study of 20 patients (10 in each group), we compared arousal with flumazenil during midazolam-narcotic anesthesia with an arousal test done during halothane-nitrous oxide anesthesia, both under conditions of controlled hypotension. Motor responses to verbal command were obtained 39.1 +/- 36.0 s (mean +/- SD) after the injection of flumazenil in eight patients. Two patients form this group awoke spontaneously 6 and 8 min after terminating the administration of nitrous oxide and midazolam but remained sedated up to the time of the test itself. In the halothane group, arousal occurred 26 +/- 8.3 min after halothane administration was terminated and 10.1 +/- 3.3 min after nitrous oxide was stopped. Two of the patients in this group moved, owing to early arousal 5 and 8 min before the scheduled time and needed reinstatement of anesthesia. In four patients in the halothane group, we had to wait 3-11 min after the scheduled time before satisfactory arousal was achieved. One of the patients in the halothane group showed a motor deficit of the lower limbs during the wake-up test that disappeared after decreasing the spine correction. There were no adverse reactions except for occasional shivering in the recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Use of flumazenil (RO 15-1788) after prolonged infusion of midazolam in anesthesia for intracranial surgery

Midazolam, with a half-life of about 1.5-3.5 h, is inappropriate for the maintenance of anaesthesia during long procedures, especially when rapid recovery is necessary. The efficacy of flumazenil, a specific benzodiazepine antagonist, in the treatment of patients with benzodiazepine overdose suggests that rapid recovery from anaesthesia induced and maintained with midazolam might be obtained in patients needing immediate assessment. The rate of recovery, the side-effects and the feasibility of an early and accurate neurological assessment were studied in 18 ASA III patients after craniotomy in whom the prolonged effects of midazolam had been antagonized by flumazenil. Surgery lasted 5.5 +/- 1.3 h (means +/- SD). The induction dose of midazolam was 0.32 +/- 0.08 mg.kg-1 and the infusion rate was 0.2 +/- 0.08 mg.kg-1.h-1. Fentanyl was added at a dose and rate of 5.0 +/- 3.6 micrograms.kg-1 and 2.0 +/- 0.9 micrograms.kg-1.h-1 respectively. At the end of the dressing, 0.5 mg of flumazenil (t0) was injected, followed by 0.1 mg every minute up to a total of 1 mg. After 2 min, 14 patients (78%) opened their eyes (p less than 0.05) and 13 (72%) obeyed orders (p less than 0.05). After 10 min, 16 patients (89%) were extubated and speaking. During the first 10 min, the Glasgow score and the sedation score used for this study showed the same progression, with 13 patients (72%) having a Glasgow score of 14-15 (p less than 0.05). Thereafter, both scores decreased progressively till t60, then increased again, reaching their t10 level at t120. Three patients required another dose of antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)     

Resedation after bolus administration of midazolam to an infant and its reversal by flumazenil

A 4-month-old infant was sedated with bolus doses of midazolam, and after initial apparent complete arousal, became unresponsive and hypotonic. Administration of flumazenil enabled differentiation of a residual drug effect from an intracerebral event.     

A comparison of the early pharmacokinetics of midazolam in pregnant and nonpregnant women

The early pharmacokinetics of midazolam were compared in pregnant (active labour, awaiting and during elective Caesarean section) and matched gynaecological patients scheduled to undergo elective hysterectomy, half of whom were given an oxytocin infusion. A standard dose of 5 mg was given intravenously. For the first 15 minutes patients in labour had significantly higher plasma midazolam levels compared to all other groups. This was associated with the largest area under the curve (2 hours), the smallest volume of distribution and lowest clearance. Midazolam when given immediately before Caesarean section, can result in depression of the infant.     

Reversal of central benzodiazepine effects by intravenous flumazenil.

The purpose of this study was to determine the efficacy of flumazenil in safely expediting patient recovery from benzodiazepine sedation. This double-blind, randomized, placebo-controlled study involved 30 patients who received conscious sedation induced by intravenous midazolam given for a dental surgical procedure. Patients who received flumazenil were rated significantly more alert than were placebo-treated patients at 5 and 15 min following test drug administration. They also had significantly superior scores on the digital symbol substitution test and on tests in a comprehensive modified neurological examination 5 min after receiving flumazenil. Group differences were not as impressive on recall and recognition tests. However, flumazenil patients scored somewhat more favorably than the placebo group patients in identifying simple objects they had been shown during the observation period following surgery. Flumazenil appears to be a promising drug for reversing midazolam conscious sedation.     

Effect of flumazenil on disturbance of equilibrium function induced by midazolam

Benzodiazepines in intravenous sedation are useful, owing to their outstanding amnesic effect when used for oral surgery as well as dental treatments on patients with intellectual disability or dental phobia. However, compared with propofol, the effect of benzodiazepine lasts longer and may impede discharge, especially when it is administered orally because of fear of injections. Although flumazenil antagonizes the effects of benzodiazepine quickly, its effect on the equilibrium function (EF) has never been tested. Since EF is more objective than other tests, the purpose of this study is to assess the sedation level and EF using a computerized static posturographic platform. The collection of control values was followed by the injection of 0.075 mg/kg of midazolam. Thirty minutes later, 0.5 mg or 1.0 mg of flumazenil was administered, and the sedation level and EF were measured until 150 minutes after flumazenil administration. Flumazenil antagonized sedation, and there was no apparent resedation; however, it failed to antagonize the disturbance in EF. This finding may be due to differences in the difficulty of assessing the sedation level and performing the EF test, and a greater amount of flumazenil may effectively antagonize the disturbance in EF.     

The use of midazolam and flumazenil in locoregional anaesthesia: an overview

Midazolam is useful as an intravenous supplement to local anaesthesia techniques in producing sedation, amnesia and anxiolysis, and has about five times the sedative potency of diazepam. Considerable interpatient variability exists in dose requirements, especially in elderly patients. The combined effects of local anaesthetics and midazolam may contribute to enhanced haemodynamic effects and changes in the respiratory pattern, impairing ventilation and oxygenation. Flumazenil can be titrated in incremental doses to reverse the residual sedative effects of midazolam, without intrinsic haemodynamic or respiratory effects, but may not fully antagonise the decrease in chemoreceptor sensitivity nor the changes in breathing pattern induced by midazolam. Patients treated with epidural or spinal anaesthesia supplemented with midazolam should be monitored to avoid hypoxaemia risks even after the administration of flumazenil.     

Flumazenil and midazolam in anaesthesia

Flumazenil, the first benzodiazepine antagonist, is currently used widely as an emergency drug, and has also been utilized in planned procedures, to time arousal intra- or post-operatively. It is known that flumazenil, used at the end of a procedure, causes instant recovery by reversing the residual effects of, for example, midazolam. An agonist-antagonist concept, midazolam-flumazenil, where benzodiazepine sedation or anaesthesia is terminated at will, is, therefore, finding increasing application. In neuroanaesthesia, for example, it facilitates immediate recovery, cardiovascular stabilization and the use of midazolam as an alternative to thiopentone and inhalational agents, and in ear, nose and throat endoscopies, it permits more rapid turnover of patients and is a good choice for haemodynamic stability in patients with a high cardiovascular risk factor. There continues to be debate over the term used to describe the level of sedation remaining after the effects of the antagonist have worn off. 'Resedation' is often used incorrectly to describe what is in reality residual sedation. Given the correct use of midazolam or the exploitation of synergism using opioids, flumazenil will cause arousal, while maintaining the benefit of opioid analgesia. Such a technique may eliminate the need for formal recovery facilities in many ambulatory patients, thereby reducing dependence on trolleys, beds and nurses. This has major implications for health economics, particularly in relation to endoscopy clinics and when co-induction of anaesthesia is employed.