Effects of the benzodiazepine antagonist flumazenil on postoperative performance following total intravenous anaesthesia with midazolam and alfentanil

Postoperative performance following total intravenous anaesthesia (TIVA) using midazolam and alfentanil was studied with and without the administration of a single dose of a benzodiazepine antagonist, flumazenil (Ro 15-1788). Performance was compared with a reference group anaesthetized with thiopentone, alfentanil and nitrous oxide. All patients were assessed by use of a rating scale which took into account the degree of sedation, amnesia, comprehension and cooperation as well as temporal and spatial orientation. There was a slow recovery following TIVA with somnolence and amnesia lasting several hours. Administration of flumazenil 1.0 mg i.v. at extubation caused a significant reduction of sedation (P less than 0.001) during the first postoperative hour, with patients fully awake or only lightly sedated, but was later followed by resedation. The patients of the reference group were moderately sedated during the observation period. Five and six hours postoperatively there was no difference between the groups. Amnesia was more profound in the groups that received midazolam; the effect of the antagonist could only be seen for 15 min after its administration. Comprehension and cooperation, as well as orientation, were equally good in the antagonist and in the reference group during the immediate postoperative period, whereas in the TIVA group a gradual improvement over the first hours was seen. In the antagonist group there was no increase in the number of analgesic requirements, no anxiety attacks or other adverse effects. It is concluded that flumazenil offers an improvement in postoperative performance following TIVA induced by midazolam and alfentanil, but the effects are of short duration.     

Total intravenous anaesthesia with midazolam and flumazenil in outpatient clinics

Total intravenous anaesthesia with midazolam and alfentanil, reversed with the benzodiazepine antagonist flumazenil, was studied in patients admitted for outpatient gynaecological dilatation and curettage. One hundred patients were randomly allocated to four groups with different anaesthetic techniques: I: alfentanil and thiopentone induction, 66% N2O maintenance; II: alfentanil and midazolam sedation prior to isoflurane and N2O induction and maintenance; III: midazolam and alfentanil induction; oxygen/air, placebo reversal; IV: midazolam and alfentanil induction, oxygen/air, flumazenil reversal. All methods of anaesthesia proved satisfactory with no serious side-effects or complications. Induction was faster in Group I (26 s) compared with Group III and IV (37-38 s) and Group I (62 s). Respiration was less depressed in Group II compared with the other groups. Recovery function was better in Group IV during the first 30 postoperative min and worse in Group III during the first 120 postoperative min compared with the other groups. Reduced performances in P-deletion and 4-choice reaction-time tests in the midazolam patients were not reversed by 0.5 mg flumazenil, suggesting that flumazenil did not antagonize all benzodiazepine effects in our patients. Postoperative amnesia was most pronounced in Group III. There was no significant difference in patient function 7 h postoperatively, at home in the evening or during the next days. We conclude that total intravenous anaesthesia with alfentanil and midazolam with flumazenil reversal is a promising technique for short outpatient anaesthetic procedures.     

The role of midazolam and flumazenil in urology

The effects of midazolam (3–10 mg im.) and their reversal by flumazenil were studied in transurethral endoscopic procedures performed using topical analgesia. In one randomised study, patients (n = 84) received either no medication or flumazenil (0.5 mg i.v.) on completion of endoscopy. Recovery was assessed subjectively. Within 15 min, 83% of those receiving flumazenil were considered ready for discharge compared with only 24% of the control group ( P <0.001). In a second randomised, double-blind, placebo-controlled trial of 44 patients, post-operative recovery was assessed using five objective psychomotor tests. Whereas the placebo group took up to 2 h to recover, those receiving flumazenil recovered fully or returned to near control values within 15 min. Sedoanalgesia - a technique combining adequate local anaesthesia with sedation (using midazolam) - has wide application in urology, and the introduction of flumazenil has major implications for the practice of day-case surgery.     

Comparison of propofol/alfentanil anaesthesia with isoflurane/N2O/fentanyl anaesthesia for renal transplantation

Total intavenous anaesthesia (TIVA) with propofol and alfentanil was compared with balanced anaesthesia (BA) in 30 uraemic patients undergoing renal transplantation. TIVA (n=15) was induced with propofol and alfentanil and maintained with propofol and alfentanil infusions, which were started immediately after induction. Thereafter the infusion rates were adjusted as needed. Ventilation was with oxygen in air. BA (n= 15) was induced with thiopentone and fentanyl and maintained with isoflurane/N20/fentanyl. Vecuronium was used for muscle relaxation in both groups. Mean infusion rates for propofol and alfentanil were 10 1.8 mg kg^-1 h^-1 and 70 9 μg kg^-1 h^-1, respectively. To control hypertension during TIVA, larger amounts of propofol and alfentanil were needed and slower recovery was observed than in previous studies in ASA 1–2 patients. Also, significantly more vecuronium was needed during TIVA than during BA ( P < 0.05). The recovery parameters were similar in both groups, except for the occurrence of nausea, which was less after TIVA. In conclusion, TIVA had no clinical advantages over BA.     

Comparison of propofol and antagonised midazolam anaesthesia for day-case surgery

A technique of midazolam/fentanyl/isoflurane/nitrous oxide anaesthesia, in which the benzodiazepine was antagonised by the specific antagonist, flumazenil, was compared with propofol/fentanyl/nitrous oxide anaesthesia for minor outpatient urological surgery. No significant difference was found in the overall ease of anaesthesia; however, using subjective (linear analogue sedation scales) and objective (letter deletion and simple reflex time) tests, recovery was found to be significantly slower for the antagonised midazolam group. For both groups, the most frequent intraoperative problem was patient movement in response to surgical stimulation and, postoperatively, headache. The midazolam group displayed the greatest degree of residual sedation at the 4-hour time of discharge and on arrival home a significantly larger number of patients in the midazolam group slept for a period. It is likely that the dose of flumazenil chosen (1 mg) was inadequate to completely antagonise the dose of midazolam (mean 17 mg) for the full duration of recovery.     

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.     

Induction agents for day-case anaesthesia A double-blind comparison of propofol and midazolam antagonised by flumazenil

Early postoperative recovery was studied using sedation scoring, measurement of flicker fusion frequency and completion of Trieger test figures in 60 male patients who presented for vasectomy under general anaesthesia as day patients. Anaesthesia was induced in groups 1 and 2 (20 patients each) with mean (SD) doses of 0.16 (0.04) mg/kg or 0.16 (0.03) mg/kg midazolam respectively; group 2 received flumazenil 0.55 (0.19) mg after completion of surgery. The remaining 20 patients (group 3) received propofol 1.50 (0.24) mg/kg. Anaesthesia was maintained with isoflurane vaporized in 33% oxygen and nitrous oxide in all patients. Flumazenil tended to improve tests of recovery after midazolam anaesthesia, but early recovery after propofol anaesthesia was associated with better psychomotor test results and less impairment of mental state as judged by sedation and amnesia scoring.     

Cognitive and psychomotor performance following isoflurane, midazolam/alfentanil and propofol anesthesia. A comparative study]

Mental and psychomotor abilities are impaired to varying degrees after general anaesthesia. This has important implications for the time over which patients are monitored in the recovery room and for the discharge of outpatients after day surgery. The present study was undertaken to compare recovery and mental and psychomotor skills in the first 60 min following general anaesthesia with isoflurane, midazolam/alfentanil and propofol. METHODS. A total of 45 patients undergoing microsurgical lumbar nucleotomy were randomized to three study groups. Group 1 (n = 15): anaesthesia was induced with thiopentone and maintained with isoflurane; group 2 (n = 15): anaesthesia was induced with midazolam and maintained with alfentanil; group 3 (n = 15): anaesthesia was induced and maintained with propofol. Vecuronium was used for muscle relaxation and the lungs were ventilated with a mixture of 66% nitrous oxide in oxygen. The following were checked 15, 30, 45, and 60 min after extubation: choice reaction times and critical flicker fusion for psychomotor testing; the maze test and a modification of the ball-bearing test for discrimination of motor and mental activities; and short- and long-term memory. RESULTS. Immediate recovery did not differ in the three different groups. In all patients psychomotor function was impaired compared with baseline for more than 60 min after general anaesthesia. However, impairment was significantly less pronounced after propofol, and recovery to preanaesthesia values was faster following propofol than after midazolam/alfentanil, and slowest after isoflurane-anaesthesia (Figs. 1, 2). The flicker fusion frequency, a very sensitive parameter for the persisting effects of anaesthetics, was significantly higher following propofol anaesthesia and remained so throughout the entire study period (Fig. 3). By 30 min after extubation, short-term memory was already normal in patients who had undergone propofol anaesthesia, and a statistically significant difference from the midazolam/alfentanil and isoflurane anaesthesia groups was obvious throughout the entire study period. However, no differences in long-term memory were found. At 30 min after propofol anaesthesia all patients were able to perform the ball-bearing test, as against 13 patients following midazolam/alfentanil and 10 patients following isoflurane (Table 3). The maze test was mostly impaired after midazolam/alfentanil anaesthesia. Patients who underwent isoflurane anaesthesia needed the same time for the maze test at 60 min afterwards propofol patients needed after 30 min (Table 2). Side effects, e.g., nausea, vomiting, and double vision, were observed significantly more often in groups 1 and 2 (Table 4). DISCUSSION AND CONCLUSION. The results indicate that in operations of approximately 90 min duration the return of motor and mental abilities is faster following propofol anaesthesia. At 30 min after extubation following propofol anaesthesia patients had test results that allow their transfer from the recovery room, while it took 60 min for patients in the two other groups to reach the same levels of motor and mental function. This is important for the duration of monitoring in the recovery room and, especially, for day case anaesthesia.     

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.     

Flumazenil in intensive care The duration of arousal after an assessment dose

The effect of an assessment dose of the benzodiazepine antagonist flumazenil was studied in 20 patients in an intensive care unit. The patients had been sedated with alfentanil and midazolam, and were ready to be weaned from mechanical ventilation. In 10 patients flumazenil was titrated just to produce full arousal whilst the midazolam infusion was continued; flumazenil administration was repeated one hour later after the infusion of midazolam had been stopped. In another 10 patients, flumazenil was administered only once, coinciding with the cessation of sedation. The duration of full arousal in both groups was less than 15 minutes in 75% of patients given a single dose of flumazenil (median dose 0.4 mg) although some effect persisted for up to 60 minutes. The cardiovascular effects of arousal were transient and probably not clinically significant. A brief duration of action is advantageous if the patient is found still to require sedation.     

Recovery from fixed–dose midazolam–induced anaesthesia and antagonism with flumazenil for outpatient arthroscopy

This study evaluated recovery after a fixed dose of midazolam as induction agent and the influence of flumazenil on recovery parameters in patients undergoing day-case surgery (arthroscopy of the knee). In 40 unpremedicated patients, anaesthesia was induced with midazolam 0.2 mg/kg, vecuronium bromide 0.1 mg/kg intravenously and 3 vol.% isoflurane in oxygen prior to intubation. Anaesthesia was maintained with nitrous oxide 66% in oxygen and 0.9 vol.% isoflurane. Ten minutes after the end of anaesthesia 20 patients received 0.2 mg flumazenil intravenously, followed by increments of 0.1 mg at 60 s intervals until eye opening. Recovery was assessed by the time to eye-opening, to answering five set questions correctly, and to recovering ocular balance (Maddox Wing test), and by comparing pre- and postoperative performance in a pencil and paper test (the p-deletion test). With the exception of ocular balance, all parameters showed a quicker improvement without side-effects in the flumazenil group. After 4 h all patients were fit for discharge. One month after the procedure, all patients were satisfied with the anaesthesia. Full recovery took on average 1.5 days (range between 0 h-10 days). Whilst the technique employing a fixed dose of midazolam as induction agent gives satisfactory intraoperative anaesthesia for day-case arthroscopy, further improvement can be made with the use of flumazenil which hastens recovery.     

Recovery from total intravenous anaesthesia. Propofol versus midazolam-flumazenil

The aim of this study was to compare recovery assessed with the Newman, deletion af a's and postbox tests after total intravenous anaesthsia for procedures lasting more than 90 min, with either propofol (PPF) or midazolam (MDZ), reversed or not by flumazenil (FMZ). Thirty patients scheduled for peripheral surgery were randomly allocated to 3 groups of 10, receiving by continuous infusion until the end of surgery either PPF (n = 10) or MDZ (n = 20) combined with alfentanil. FMZ was administered thereafter to 10 patients receiving MDZ until they opened their eyes on command or to a maximum dose of 1 mg. Recovery tests were performed 45, 90 and 180 min after the end of anaesthesia. Results were analysed with non-parametric tests. Recovery scores were significantly better in the PPF group at all times, reaching control values at 180 min for the three first tests. FMZ reversal did not improve the scores compared to those resulting from MDZ alone. This study provides further data in favour of PPF as far as rapid and complete recovery is concerned. The efficiency of FMZ is incomplete and only transient when administered in a single dose.     

Remifentanil vs alfentanil in the total intravenous anaesthesia for paediatric abdominal surgery

BACKGROUNDS: Our aim was to investigate whether total intravenous anaesthesia (TIVA) with remifentanil and alfentanil would ensure appropriate analgesia and recovery conditions in anaesthesia for children undergoing abdominal surgery. METHODS: Sixty children, scheduled for abdominal operations were randomized to receive, in a double-blind manner, either remifentanil (loading dose 1 microg x kg(-1); maintenance infusion, 0.25 microg x kg(-1) min(-1)) or alfentanil (loading dose 50 microg x kg(-1); maintenance infusion, 1 microg x kg(-1) min(-1)) as the analgesic component of TIVA. They were combined with propofol (loading dose, 2 mg x kg(-1); step 1 maintenance infusion, 10 mg x kg(-1) h(-1); step 2 maintenance infusion, 8 mg x kg(-1) h(-1); step 3 maintenance infusion, 6 mg x kg(-1) h(-1)) neuromuscular blockade was with mivacurium. Dose changes of the drugs, the times from cessation of anaesthesia to extubation, verbal responses, recovery of ventilation, orientation, and qualification for discharge from the postanaesthetic care unit (PACU) were recorded. RESULTS: Demographics, duration of surgery and anaesthesia were similar between the two groups. Times to extubation and stay in the PACU were significantly shorter in the remifentanil group compared with the alfentanil group. Quality of emergence (QE) from anaesthesia scale scores were higher in the remifentanil group compared with the alfentanil group. CONCLUSIONS: Remifentanil provides a more rapid recovery and adequate postoperative analgesia after TIVA for paediatric abdominal surgery, compared with alfentanil.     

Oxygen consumption after flumazenil reversal

The effect of flumazenil reversal of midazolam-induced anesthesia on whole body oxygen uptake (VO2) was investigated in a double-blind trial in 48 patients (ASA, 1 or 2) undergoing elective surgery under general anesthesia. VO2 was measured in spontaneously breathing patients during recovery from anaesthesia induced with midazolam 0.25 mg.kg-1 and maintained with nitrous oxide 60% in oxygen and halothane. The level of sedation was evaluated by a subjective score. To reverse midazolam-induced anesthesia, patients were randomly allocated to receive placebo or flumazenil (6 micrograms.kg-1). No significant changes in VO2 (160 +/- 53 vs 150 +/- 39 ml.min-1.m-2 or sedation score (2.5 +/- 1.0 vs 2.1 +/- 0.9) were observed in the placebo group. After flumazenil administration, the sedation score significantly (P less than 0.05) improved (2.9 +/- 1.0 vs 1.3 +/- 0.8) whereas no significant change in VO2 was observed (158 +/- 67 vs 157 +/- 61 ml O2.min-1.m-2). These data show that reversal of benzodiazepine effects with flumazenil resulted in no significant change in oxygen uptake.     

Anaesthesia with Midazolam/Medetomidine/Fentanyl in Chinchillas (Chinchilla lanigera) Compared to Anaesthesia with Xylazine/Ketamine and Medetomidine/Ketamine

We studied four different drug regimes for anaesthetic management in chinchillas and evaluated and compared their cardiovascular and respiratory effects. In this randomized, cross‐over experimental study, seven adult chinchillas, five females, two males [515 ± 70 (SD) g] were randomly assigned to one of the following groups: group 1 [midazolam, medetomidine and fentanyl (MMF), flumazenil, atipamezole and naloxone (FAN); MMF–FAN] received 1.0 mg/kg midazolam, 0.05 mg/kg medetomidine and 0.02 mg/kg fentanyl i.m., and for reversal 0.1 mg/kg flumazenil, 0.5 mg/kg atipamezole and 0.05 mg/kg naloxone s.c. after 45 min; group 2 (MMF) 1.0 mg/kg midazolam, 0.05 mg/kg medetomidine and 0.02 mg/kg fentanyl i.m.; group 3 [xylazine/ketamine (X/K)] 2.0 mg/kg xylazine and 40.0 mg/kg ketamine i.m.; and group 4 [medetomidine/ketamine (M/K)] 0.06 mg/kg medetomidine and 5.0 mg/kg ketamine i.m. Reflexes were judged to determine anaesthetic stages and planes. Anaesthesia with X/K and M/K was associated with a prolonged surgical tolerance and recovery period. By reversing MMF, recovery period was significantly shortened (5 ± 1.3 min versus 40 ± 10.3 min in MMF without FAN, 73 ± 15.0 min in X/K, and 31 ± 8.5 min in M/K). Without reversal, MMF produced anaesthesia lasting 109 ± 16.3 min. All combinations decreased respiratory and heart rate but compared with X/K and M/K, respiratory and cardiovascular complications were less in the MMF groups. Focussing on the clinical relevance of the tested combinations, completely reversible anaesthesia showed two major advantages: anaesthesia can be antagonized in case of emergency and routinely shortens recovery. In small animals particularly these advantages lead to less complications and discomfort and thus often can be lifesaving. As all analgesic components (medetomidine and fentanyl) are reversed, postoperative analgesia should be provided before reversal of anaesthesia.     

Flumazenil in total intravenous anaesthesia using midazolam and fentanyl

Forty patients, scheduled for elective surgery in a thoracic and vascular surgical unit, were anaesthetized by a total intravenous anaesthesia technique using midazolam and fentanyl. Subsequent reversal of anaesthesia by the specific benzodiazepine antagonist flumazenil was evaluated in a double-blind trial. The patients were observed in the recovery room postoperatively until the next morning, and their recovery was repeatedly evaluated during the first 240 min after anaesthesia. Six patients in the placebo group required an oral airway or an endotracheal tube during the first hours of recovery, whereas none who received flumazenil did. The respiratory rate was significantly higher after flumazenil than placebo during the first 4 h postoperatively (Anova, P less than 0.01). Blood pressure and heart rate were not different between the two groups. The degree of sedation, orientation in time and space and the ability to cooperate were significantly superior after flumazenil than placebo (Anova, P less than 0.01). Some degree of resedation was observed in both groups, affecting 95% of the patients who received flumazenil against 30% after placebo (Mann-Whitney, P less than 0.05). No adverse reactions attributable to the use of flumazenil were encountered.     

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.     

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.     

A comparison of two different doses of ketamine with midazolam and midazolam alone as oral preanaesthetic medication on recovery after sevoflurane anaesthesia in children

BACKGROUND: This investigation prospectively evaluated the effect of oral premedication of two different doses of ketamine with midazolam and midazolam alone on the recovery of children after sevoflurane anaesthesia. METHODS: In a randomized, double-blind study, 79 children (aged 1-8 years, ASA physical status I or II) were assigned to receive one of three premedications in a volume of 0.5 ml x kg(-1): group 1 received midazolam 0.5 mg x kg(-1) (MD); group 2 received midazolam 0.5 mg x kg(-1) with ketamine 1.8 mg x kg(-1) (MK-1); and group 3 received midazolam 0.5 mg x kg(-1) with ketamine 3 mg x kg(-1) (MK-2). The reactions of the children during administration were noted. Anaesthesia was induced by facemask with incremental sevoflurane administration. All children received alfentanil (15 micro g x kg(-1)). Tracheal intubation was facilitated by mivacurium (0.2 mg x kg(-1)). Anaesthesia was maintained with sevoflurane and an additional dose of alfentanil, if necessary. During recovery, the time interval between discontinuation of anaesthesia and arousal (spontaneous ventilation, extubation) were recorded. RESULTS: Emergence (spontaneous ventilation, extubation) and recovery times (discharge, Aldrete score=9) did not differ significantly between groups (P=0.24, P=0.59 and P=0.145, respectively). CONCLUSIONS: The combination of midazolam and ketamine as oral preanaesthetic medication did not significantly affect the recovery time of children after sevoflurane anaesthesia.     

Benzodiazepine antagonism does not provoke a stress response

Acute anxiety reactions have been reported following antagonism of benzodiazepine-induced sedation. In this study, the level of sedation and anxiety was assessed in 30 patients randomly assigned to receive either saline or flumazenil (a benzodiazepine antagonist) after midazolam sedation according to a double-blind protocol. Carefully titrated doses of flumazenil, 0.8 +/- 0.2 mg (mean +/- SD), effectively reversed residual midazolam-induced sedation without producing significant changes in the patients' level of anxiety. In addition, plasma epinephrine, norepinephrine, vasopressin, and beta-endorphin concentrations were measured in a subset of patients (n = 5) from each group. The levels of these stress hormones did not acutely change following flumazenil (or saline). These results indicate that flumazenil, 0.6-1.0 mg iv, can antagonize midazolam sedation without producing acute anxiety or evidence of a stress response.