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PubMed2005

Midazolam for patients undergoing upper gastrointestinal endoscopy: a prospective, single-blind and randomized study to determine the appropriate amount and time of initiation of endoscopy.

BACKGROUND AND AIMS: Midazolam is currently the most used sedative agent in endoscopy. The present study was designed to examine the appropriate dose of midazolam, time of initiation of endoscopy after midazolam infusion, and to prove the necessity of flumazenil as an antidote. METHODS: One hundred and eighty patients undergoing diagnostic gastroscopy were assigned three different amounts of intravenous midazolam in prospective, single-blinded and randomized setting as follows: (i) group I 0.03 mg/kg midazolam; (ii) group II 0.06 mg/kg midazolam; and (iii) group III 0.09 mg/kg midazolam. Endoscopy was initiated 30, 60 and 90 s after infusion of midazolam within each group. After endoscopy, patients were divided into two groups, one receiving flumazenil and one placebo in a double-blind fashion. The ease of the procedure, the conscious sedative state, the paradoxical response, the level of satisfaction and anterograde amnesia were assessed using a 100 mm visual analog scale. RESULTS: The endoscopist's assessments were not changed by the different doses of midazolam; however, significant differences were observed in the paradoxical responses (P < 0.05). The level of satisfaction with endoscopy was notably different between group I and the other two groups (P < 0.05). Amnesia was boosted according with increasing doses of midazolam (P < 0.05). The time until discharge after endoscopy was significantly different between group III and the other two groups (P < 0.05) and the discharge time was reduced in the flumazenil subgroup compared with the placebo subgroup in group III (P < 0.05). Group II (0.06 mg/kg) reported good levels of satisfaction, fewer paradoxical responses and short discharge time without any side-effects. Comparing the time of initiation of endoscopy (at 30, 60 and 90 s after midazolam) in each group, there were no significant differences in the level of satisfaction, conscious sedative state and amnesia. CONCLUSIONS: Midazolam should be administered at a dose of 0.06 mg/kg and the endoscopy should be initiated 30 s after midazolam injection for appropriate effects without any side-effects. Flumazenil is not necessary, except in the case of the use of a high dose (above 0.09 mg/kg) of midazolam.

Analysis of Variance↗
PubMed1993

Benzodiazepine withdrawal reaction in two children following discontinuation of sedation with midazolam.

OBJECTIVE: To report the occurrence of recurrent benzodiazepine withdrawal reactions in two very young children following discontinuation of sedation with midazolam. CASE SUMMARY: A 15-month-old boy with apneic episodes was sedated with midazolam for 12 days with constant infusion. Half a day after discontinuation of the midazolam the boy became restless, tachycardic, and hyperpyrexic. When midazolam was readministered, all symptoms disappeared. Four days later midazolam was again discontinued and within 12 hours the same signs and symptoms reappeared. Midazolam infusion was restarted, and the signs and symptoms disappeared for the second time. After thoracotomy, a 14-day-old boy received intravenous midazolam for sedation for 29 days. Within 12 hours after discontinuation of midazolam he became restless, developed a bulging stomach secondary to aerophagia, and was vomiting. Midazolam therapy was reinstituted and continued for another 2 months by constant infusion. Thereafter, the boy was successfully weaned from artificial ventilation in 5 days under sedation with midazolam. About 12 hours after discontinuation of midazolam the boy became restless, tachycardic, again developed a bulging stomach because of aerophagia, and vomited. When the child was sedated with clorazepate by continuous infusion, the signs and symptoms disappeared. DISCUSSION: Case reports describing benzodiazepine withdrawal reaction upon discontinuation of midazolam were reviewed and compared. The symptoms observed in the children we present resemble those mentioned in the three children and two adults reported previously. Unique in the very young children in this article is the occurrence of gastrointestinal symptoms, which most likely are the result of air being swallowed secondary to severe agitation. CONCLUSIONS: Midazolam withdrawal reactions in adults and children, particularly in an intensive care unit, can be significant. Considerable caution must be taken with relatively long-term administration and abrupt discontinuation of midazolam.

Aerophagy↗
PubMed1985

Midazolam oral self-administration.

The technique of chronic schedule-induced drug solution intake was used to determine the possible addiction liability of the short-acting benzodiazepine midazolam. Schedule-induction produces polydipsia over a wide range of fluids as a function of the imposed schedule of food availability. The inducing schedule used presented food pellets automatically once per minute, fixed time (FT) 1-min, for 3 h daily. Two groups of rats, drinking either water or 0.05 mg/ml midazolam solution, were exposed to schedule-induction sessions for approx. 2 months. Then, other FT-values (0, 0.5, 3 and 5 min) were instituted on occasion for single sessions. Each of these 'probe' session determinations was done twice. Although midazolam concentration had been adjusted so that the mean group intakes were equal at FT 1-min, probe values greater than 1 min revealed a greater acceptance of midazolam compared to water. This technique produced session midazolam intakes as great as 25 mg/kg. In the next phase, the entire experiment was repeated except both groups were offered a choice between water and midazolam solution during sessions. Only at FT 0 and FT 5-min was there an indication that midazolam was preferred over water. Two additional groups of animals were exposed to the same schedule-induced polydipsia regimen, drinking water and midazolam solution, respectively. Pre-session administration of doses of Ro 15-1788, CGS 8216 (benzodiazepine antagonists) or midazolam had no effects on either water or midazolam intakes, although the higher dose of midazolam (2 mg/kg, s.c) had a moderately suppressive effect on the non-tolerant water-polydipsic group. All groups were tested on occasion for physical dependence on midazolam with an auditory stimulus as the precipitator and midazolam polydipsic groups were found to have a mild to moderate dependence (clonic seizures, running fits).

Administration, Oral↗
PubMed1996

Effect of chronic treatment with morphine, midazolam, and both together on beta-endorphin levels in the rat.

We have recently reported that a short-acting anesthetic and analgesic drug midazolam can produce analgesia and decrease morphine tolerance and dependence in the rat by interacting with the opioid system. This study was designed to investigate the effect of midazolam, morphine, and both together on beta-endorphin levels in the rat. Male Sprague-Dawley rats were divided into four groups: (1) saline-saline; (2) saline-morphine; (3) midazolam-saline, and (4) midazolam-morphine groups. First, saline or midazolam injection was given IP and after 30 min a second injection of saline or morphine was given subcutaneously once daily for 11 days. Animals were sacrificed on 11th day 60 min after the last injection, to measure beta-endorphin by radioimmunoassay. Saline-morphine-treated animals showed a significant increase in beta-endorphin levels in the cortex, pons, medulla, lumbar spinal cord, adrenals, and spleen, and a decrease only in its level in pituitary. Midazolam-saline-treated animals showed a significant increase in beta-endorphin levels only in the medulla, and a decrease in its levels in hippocampus, striatum, and adrenals. Saline-morphine-treated animals did not show any changes in plasma beta-endorphin, but animals treated with midazolam-saline had a significant decrease in plasma beta-endorphin. In rats treated with morphine and midazolam together, beta-endorphin levels in cortex, lumbar spinal cord, and spleen decreased to the similar levels observed in rats treated with saline-saline; in pons and cervical spinal cord the levels were even lower than that found in saline-saline group. The decrease in pituitary beta-endorphin in morphine-midazolam-treated rats was due to morphine's own activity, whereas the decrease in plasma beta-endorphin in hippocampus in the morphine-midazolam group was a synergistic effect of morphine and midazolam. The beta-endorphin level in adrenal glands in the morphine-midazolam-treated animals was not different from that found in rats treated with morphine alone but was still higher than that in the saline-saline group. In general, it appears that chronic treatment with morphine stimulates the beta-endorphinergic system. A concomitant treatment with midazolam abolishes the stimulatory effect of morphine on the beta-endorphinergic system. These results may help us in understanding the intrinsic mechanisms involved in narcotic tolerance and dependence.

Animals↗
PubMed1996

The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam.

We studied the interaction of azole antimycotics with intravenous (IV) and oral midazolam using a cross-over design in 12 volunteers, who ingested placebo, itraconazole, or fluconazole for 6 days. A 7.5-mg dose of midazolam was ingested on the first day, 0.05 mg/kg was administered IV on the fourth day, and 7.5 mg orally on the sixth day. Itraconazole reduced the clearance of IV midazolam by 69% and fluconazole reduced the clearance of IV midazolam by 51% (P < 0.001). A single dose of itraconazole and fluconazole increased the area under the oral midazolam concentration-time curve [AUC(0-infinity)] 3.5-fold (P < 0.001) and the peak concentration two-fold (P < 0.05) compared to placebo. On the sixth day the AUC(0-infinity) of oral midazolam was almost seven times greater with itraconazole (P < 0.001) and 3.6 times greater with fluconazole (P < 0.001) than without the antimycotics. The psychomotor effects of midazolam were also profoundly increased (P < 0.001). The psychomotor tests demonstrated only a weak interaction between the antimycotics and IV midazolam. When bolus doses of midazolam are given for short- time sedation, the effect of midazolam is not increased to a clinically significant degree by itraconazole and fluconazole, and it can be used in normal doses. However, the use of large doses of IV midazolam increases the risk of clinically significant interactions also after IV midazolam. Use of oral midazolam with itraconazole and fluconazole should be avoided.

Administration, Oral↗
PubMed1982

Comparative evaluation of intravenous agents for rapid sequence induction--thiopental, ketamine, and midazolam.

The pharmacologic effects of ketamine, midazolam, and a midazolam-ketamine combination were compared with thiopental for rapid induction of general anesthesia. Thiopental, 4 mg/kg, 1.5 mg/kg ketamine, 0.3 mg/kg midazolam, or 0.15 mg/kg midazolam, and 0.75 mg/kg ketamine, were administered intravenously in a randomized fashion to 80 patients undergoing emergency surgery. Adequacy of induction, hemodynamic changes, and postoperative effects were assessed during and after a standardized induction-maintenance anesthetic technique. Midazolam had the slowest onset (15-60 s) and longest duration of action. During induction, thiopental decreased mean arterial pressure (MAP) by 11%, ketamine increased MAP by 10%, while neither midazolam nor the midazolam-ketamine combination significantly changed MAP. Heart rate (HR) increased during induction in all groups; however, the increase was significantly less in the combination group. After intubation, MAP and HR increased to the same extent in all four groups. Significantly more patients who received ketamine for induction were disoriented during emergence. Midazolam most effectively produced anxiolysis and antegrade amnesia. Significantly more patients who received thiopental felt depressed postoperatively, and 95% required parenteral opiate analgesics in the recovery room. Dreaming was highest after ketamine (55%) and lowest after midazolam (0%) and the combination (5%). Thus, midazolam effectively attenuated both the cardiostimulatory responses and unpleasant emergence reactions associated with ketamine. The author concludes that both midazolam and the midazolam-ketamine combination are safe and effective induction agents for emergency surgery, which may offer an advantage over thiopental in situations where hemodynamic stability is crucial. Furthermore, midazolam effectively attenuates the side effects of ketamine.

Adult↗
PubMed1997

Prolonged sedation of critically ill patients with midazolam or propofol: impact on weaning and costs.

OBJECTIVE: To compare the effectiveness of sedation, the time required for weaning, and the costs of prolonged sedation of critically ill mechanically ventilated patients with midazolam and propofol. DESIGN: Open-label, randomized, prospective, phase IV clinical trial. SETTING: Medical and surgical intensive care unit (ICU) in a community hospital. PATIENTS: All ICU admissions (medical, surgical and trauma) requiring mechanical ventilation for > 24 hrs. A total of 108 patients were included in the study. INTERVENTIONS: Patients were randomized to receive midazolam or propofol. The dose range allowed for each drug was 0.1 to 0.5 mg/kg/hr for midazolam and 1 to 6 mg/kg/hr for propofol. The lowest dose that achieved an adequate patient-ventilator synchrony was infused. All patients received 0.5 mg/kg/24 hrs of morphine chloride. MEASUREMENTS AND MAIN RESULTS: The level of sedation was quantified by the Ramsay scale every 2 hrs until weaning from mechanical ventilation was started. If sedation could not be achieved by infusing the highest dose of midazolam or propofol, the case was recorded as a therapeutic failure. In the propofol group, serum triglycerides were determined every 72 hrs. Concentrations of > 500 mg/dL were also recorded as a therapeutic failure. When the patient was ready for weaning according to defined criteria, sedation was interrupted abruptly and the time from interruption of sedation to the first T-bridge trial and to extubation was measured. Cost analysis was performed based on the cost of intensive care in our unit ($54/hr). In the midazolam group (n = 54), 15 (27.8%) patients died; 11 (20.4%) patients had therapeutic failure; and 28 (51.8%) patients were subjected to a T-bridge trial. In the propofol group (n = 54), these proportions were 11 (20.4%), 18 (33.4% [including seven due to inadequate sedation, and 11 due to hypertriglyceridemia]), and 25 (46.2%), respectively. None of these values was significantly different between the two groups. Duration of sedation was 141.7 +/- 89.4 (SD) hrs and 139.7 +/- 84.7 hrs (p = NS), and cost (US dollars) attributed to sedation was $378 +/- 342 and $1,047 +/- 794 (p = .0001) for the midazolam and propofol groups, respectively. In the midazolam group, time from discontinuation of the drug infusion to extubation was 97.9 +/- 54.6 hrs (48.9 +/- 47.2 hrs to the first disconnection, and 49.0 +/- 23.7 hrs to extubation). In the propofol group, time from discontinuation of the drug infusion to extubation was 34.8 +/- 29.4 hrs (4.0 +/- 3.9 hrs to the first disconnection, and 30.8 +/- 29.2 hrs to extubation). The difference between the two groups in the weaning time was 63.1 +/- 12.5 (SEM) hrs (p < .0001). Cost per patient in the midazolam group (including ICU therapy and sedation with midazolam) was $10,828 +/- 5,734. Cost per patient in the propofol group was $9,466 +/- 5,820, $1,362 less than in the midazolam group. CONCLUSIONS: In our population of critically ill patients sedated with midazolam or propofol over prolonged periods, midazolam and propofol were equally effective as sedative agents. However, despite remarkable differences in the cost of sedation with these two agents, the economic profile is more favorable for propofol than for midazolam due to a shorter weaning time associated with propofol administration.

Adult↗
PubMed2003

Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients.

OBJECTIVE: To determine the pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. DESIGN: Prospective population pharmacokinetic study. SETTING: Pediatric intensive care unit. PATIENTS: Twenty-one pediatric intensive care patients aged between 2 days and 17 yrs. INTERVENTIONS: The pharmacokinetics of midazolam and metabolites were determined during and after a continuous infusion of midazolam (0.05-0.4 mg/kg/hr) for 3.8 hrs to 25 days administered for conscious sedation. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken at different times during and after midazolam infusion for determination of midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide concentrations via high-performance liquid chromatography-ultraviolet detection. A population analysis was conducted via a two-compartment pharmacokinetic model by the NPEM program. The final population model was used to generate individual Bayesian posterior pharmacokinetic parameter estimates. Total body clearance, apparent volume distribution in terminal phase, and plasma elimination half-life were (mean +/- sd, n = 18): 5.0 +/- 3.9 mL/kg/min, 1.7 +/- 1.1 L/kg, and 5.5 +/- 3.5 hrs, respectively. The mean 1-OH-midazolam/midazolam ratio and (1-OH-midazolam + 1-OH-midazolam-glucuronide)/midazolam ratio were 0.14 +/- 0.21 and 1.4 +/- 1.1, respectively. Data from three patients with renal failure, hepatic failure, and concomitant erythromycin-fentanyl therapy were excluded from the final pharmacokinetic analysis. CONCLUSIONS: We describe population and individual midazolam pharmacokinetic parameter estimates in pediatric intensive care patients by using a population modeling approach. Lower midazolam elimination was observed in comparison to other studies in pediatric intensive care patients, probably as a result of differences in study design and patient differences such as age and disease state. Covariates such as renal failure, hepatic failure, and concomitant administration of CYP3A inhibitors are important predictors of altered midazolam and metabolite pharmacokinetics in pediatric intensive care patients. The derived population model can be useful for future dose optimization and Bayesian individualization.

Adolescent↗
PubMed1992

Pharmacokinetic-EEG effect relationship of midazolam in aging BN/BiRij rats.

1. The purpose of the present investigations was to determine the influence of increasing age on the pharmacokinetics and pharmacodynamics of midazolam in male BN/BiRij rats as an animal model of aging. 2. Midazolam was administered intravenously at a dose of 2.5 mg kg-1 and its pharmacokinetics were determined on the basis of plasma concentrations as measured by high performance liquid chromatography (h.p.l.c.). Pharmacodynamics were studied using the midazolam-induced changes in the electro-encephalogram (EEG) as a measure of the pharmacological effect. Results were evaluated on the basis of simultaneous pharmacokinetic-pharmacodynamic modelling. In an attempt to differentiate between the effects of aging and of concurrent disease, an extensive clinical biochemical/pathological examination was conducted in individual rats by an independent pathologist. 3. The pharmacokinetics of midazolam were best characterized on the basis of a two exponential model. In the 4-month-old rats the values of the clearance, volume of distribution and elimination half-life were 104 +/- 13 ml min-1 kg-1 (mean +/- s.e. mean), 3.4 +/- 0.7 l kg-1 and 30 +/- 3 min, respectively. With increasing age, no changes in the pharmacokinetics of midazolam were observed. 4. The pharmacodynamics of midazolam were determined on the basis of the sigmoidal Emax model. In the 4-month-old rats the values of the parameters relative maximum effect, midazolam concentration at half maximum effect and Hill factor were 106 +/- 10%, 50 +/- 6 micrograms l-1 and 1.6 +/- 0.3, respectively. In the group as a whole no significant changes in the pharmacodynamic parameters of midazolam were observed.4. The pharmacodynamics of midazolam were determined on the basis of the sigmoidal Emax model. In the 4-month-old rats the values of the parameters relative maximum effect, midazolam concentration at half maximum effect and Hill factor were 106 +/- 10%, 50 +/-6 lg 1' and 1.6 +/- 0.3, respectively. In the group as a whole no significant changes in the pharmacodynamic parameters of midazolam were observed. However, when diseased animals were excluded from the evaluation, a tendency towards a decrease in the midazolam concentration at half maximum effect to 25 +/- 14 pg 1-1 was observed in the 36-month-old rats.5. These findings suggest, that increasing age is associated with a tendency towards an increased brain sensitivity to midazolam, which is reflected in a parallel shift of the concentration vs. EEG effect relationship towards lower concentrations. However, it appears that factors other than age also contribute to interindividual variability in pharmacodynamics, considering the substantial interindividual variability within certain age groups.

Aging↗
PubMed2001

The single-dose pharmacokinetics of midazolam and its primary metabolite in pediatric patients after oral and intravenous administration.

The first-dose pharmacokinetics of midazolam and its primary alpha-hydroxymetabolite were studied after single-dose administration. Eligible study patients were enrolled into one of three study arms: Arm I (midazolam/metabolite pharmacokinetic evaluation after oral administration of a syrup formulation), Arm II (the absolute bioavailability of midazolam syrup), and Arm III (midazolam and metabolite pharmacokinetics after IV administration). Complete blood sampling for pharmacokinetic analysis was available in 87 subjects. Midazolam absorption after administration of the oral syrupformulation was rapid, with adolescents absorbing the drug at approximately half the rate observed in younger children (ages 2 to < 12 years). Furthermore, midazolam t 1/2 was prolonged and CL/F reducedin adolescents as compared with younger children. Although the midazolam Vd/F appeared larger in the youngest age group after oral administration, this observation was not apparent after IV dosing, suggesting subject differences in bioavailability rather than distribution. Like midazolam, the disposition characteristics for a-hydroxymidazolam were also highly variable, with the greatest formation of metabolite (reflected by the AUC ratio) observed in children ages 2 to < 12 years. The A UC ratios of alpha-hydroxymidazolam to midazolam after IV dosing were similar across all age groups and were smaller than corresponding values following oral administration. The absolute bioavailability of midazolam averaged 36% with a very broad range (9%-71%). No relationship between midazolam bioavailability and age was observed. Overall, the disposition characteristics of midazolam and its a-hydroxy metabolite were highly variable, appeared independent of age and dose administered, and were linear over the dose range studied (0.25 to 1 mg/kg). These data suggest that an initial oral dose of 0.2 to 0.3 mg/kg should be adequateforsuccessful sedation of most pediatric patients. The inherent variability in midazolam bioavailability and metabolism underscores the importance of titrating midazolam dose to desired effect.

Administration, Oral↗
PubMed2002

Effect of 7-day exposure to midazolam on electroencephalogram pharmacodynamics in rats: a model to study multiple pharmacokinetic-pharmacodynamic relationships in individual animals.

The objective of this study was to determine the concentration-electroencephalogram (EEG) relationships for midazolam, a full-agonist benzodiazepine ligand, on multiple occasions in individual rats, and to examine the effect of chronic midazolam exposure on that relationship. Rats were chronically instrumented with venous and arterial cannulas, and cortical EEG electrodes. The rats received either: 7 days of midazolam 10 mg kg(-1) intravenously once a day (midazolam group); or midazolam on days 1 and 7 and vehicle on days 2-6 (vehicle group). Concentration-effect relationships were determined on days 1, 4 and 7 from multiple blood and EEG samples before and after the administration of the midazolam dose. The concentration-EEG effect relationships were consistent with a sigmoidal Emax (maximal effect) model. No differences in pharmacokinetic or pharmacodynamic parameters were found between day 1 and day 7 in either group. However, in the midazolam group, both the fraction unbound of midazolam in serum and the EC50 (concentration at half-maximal effect) for free midazolam increased from days 1-7 by 35 +/- 3% and 54 +/- 25%, respectively (means +/- s.d., P< 0.05). This may be related to decreased serum albumin levels in the midazolam group (-19+5%, P < 0.05) which, in turn, could be explained by the sedation associated with daily midazolam treatment. We concluded that concentration-EEG effect relationships can be studied on multiple occasions in individual animals, reducing animal use and variability. A modest degree of tolerance to midazolam was found with this paradigm, the effect only being evident after correction for the fraction unbound of midazolam.

Animals↗
PubMed1989

Discriminative stimulus properties of midazolam in the pigeon.

Five pigeons were trained to discriminate injections of midazolam (1.0 or 3.0 mg/kg i.m.) from saline with responding maintained under a fixed-ratio 30 schedule of food delivery. When other benzodiazepines were tested, they consistently produced greater than 80% of midazolam-appropriate responding. The order of potency for substituting for midazolam was triazolam greater than alprazolam = diazepam = lorazepam greater than midazolam greater than flurazepam = nitrazepam greater than nordiazepam. The barbiturate phenobarbital (10-100 mg/kg) substituted for midazolam in three of four pigeons whereas pentobarbital (1.0-30 mg/kg) substituted in only two of five pigeons. Several nonbenzodiazepine anxiolytics were also evaluated. Methaqualone (3.0-56 mg/kg) substituted in only one of four pigeons and meprobamate (30-100 mg/kg) failed to substitute in any pigeon tested. CL 218,872, when administered either i.m. (0.3-30 mg/kg) or p.o. (1.0-56 mg/kg), and buspirone (0.3-30 mg/kg) did not substitute for midazolam. Compounds from pharmacological classes not related to midazolam also failed to substitute for midazolam. Pretreatment with the benzodiazepine antagonist flumazenil (Ro 15-1788; 0.03-1.0 mg/kg) antagonized the discriminative stimulus properties of midazolam in a dose-related manner in all pigeons tested. However, this antagonism could not be overcome with increasing doses of midazolam in all pigeons. The results of the present study demonstrate that midazolam is an effective discriminative stimulus in the pigeon. Benzodiazepine anxiolytics, but not other compounds with sedative and/or anxiolytic properties, were found to reliably substitute for midazolam. These results suggest that the discriminative stimulus effects of midazolam are pharmacologically selective.

Animals↗
PubMed1988

[Continuous sedation for regional anesthesia with propofol (Disoprivan) and midazolam (Dormicum). A comparative study].

UNLABELLED: Propofol was compared to midazolam with regard to its quality as a sedative in regional anesthesia. 81 patients undergoing varicose-vein stripping under epidural anesthesia were divided into two groups: 39 were given propofol and 42 were given midazolam. Both groups were then subdivided into 3 subgroups. 30 min after epidural block, a bolus of propofol 1 mg/kg or midazolam 0.03 mg/kg was given followed by infusion of equipotent solutions: propofol 1.0, 1.5, or 2.0 mg/kg/h or midazolam 0.03, 0.045, 0.06 mg/kg/h. Continuous registration of blood pressure, respiratory rate, and end-expiratory pCO2 was carried out and blood gas analysis was performed every 30 min. RESULTS: Clinically unimportant changes of circulatory and respiratory parameters were seen. Blood gas analyses showed hypercapnia greater than 50 mmHg in some patients. Brief apnea occurred after bolus propofol in 7.7% of cases and pain during injection in 66.6%. Restlessness: propofol 28.2%, midazolam 9.5%. Upper airway obstruction: propofol 30.8%, midazolam 57.1%. Recovery time after infusion ranged from 130 s with propofol to 26 min with midazolam. Postoperative evaluation included the following questions and responses: Sedation pleasant? propofol 97.5%, midazolam 100%. Sleep during surgery? propofol 94.8%, midazolam 83.5%. Prolonged tiredness? propofol 25.6%, midazolam 69%. Postoperative nausea? propofol 38.5%, midazolam 14.2%. Vomiting? propofol 17.9%, midazolam 11.9%. Our study showed that propofol is highly suitable as a sedative for regional anesthesia in spite of injection pain and frequent postoperative nausea. It is superior to midazolam because of the significantly shorter recovery time, providing improved control-lability and reduced posthypnotic sleep.

Anesthesia, Conduction↗
PubMed1994

Azithromycin does not alter the effects of oral midazolam on human performance.

Since macrolide antibiotics inhibit the oxidative hepatic metabolism of various drugs, including midazolam, the present double blind studies were conducted to find out if azithromycin, a new macrolide of the azalide type, would inhibit the metabolism of midazolam and enhance the effects of midazolam on human performance. In Study I, 64 healthy medical students, divided in four parallel groups received placebo, midazolam (10 mg or 15 mg), and midazolam 10 mg combined with azithromycin (500 mg + 250 mg). In Study II, three males received oral midazolam 10 mg in combination with placebo, azithromycin or erythromycin 750 mg (as a positive control) in a cross-over trial. Objective and subjective tests were done before the intake of midazolam and 30 and 90 min after it, and venous blood was sampled for the assay of midazolam. In the placebo group in Study I, the mean numbers of letters cancelled (LC) at baseline, 30 min and 90 min were 21, 20 and 20, respectively, and the corresponding mean numbers of correct digit symbol substitutions (DSS) were 126, 137 and 140, indicating a practice effect. Midazolam 10 mg impaired these performances (21, 13 and 12 for LC, and 127, 113 and 111 for DSS). Either dose of midazolam produced clumsiness, mental slowness and poor subjective performance, midazolam 15 mg being slightly more active. The corresponding, scores in the azithromycin+midazolam group were 21, 16, 16 for LC, and 132, 121 and 119 for DSS, the only significant difference from placebo being the impairment of DSS at 90 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Pharmacodynamic modeling of the electroencephalographic effects of flumazenil in healthy volunteers sedated with midazolam.

The purpose of this study was to model pharmacodynamically the reversal of midazolam sedation with flumazenil. Ten human volunteers underwent four different sessions. In session 1, individual midazolam pharmacokinetics and electroencephalographic pharmacodynamics were determined. In sessions 2 and 3, a computer-controlled infusion of midazolam with individual volunteer pharmacokinetic data was administered, targeting a plasma concentration corresponding to a light or deep level of sedation (20% or 80% of the maximal midazolam electroencephalographic effect) for a period of 210 minutes. After obtaining a stable electroencephalographic effect and constant midazolam plasma concentrations, a zero-order infusion of flumazenil was started until complete reversal of midazolam electroencephalographic effect was obtained. The flumazenil infusion was then stopped and the volunteer was allowed to resedate because of the constant midazolam drug effect. The electroencephalographic response was measured during a 180-minute period and analyzed by aperiodic analysis and fast-Fourier transforms. In session 4, a midazolam plasma concentration corresponding to a deep level of sedation was targeted for 210 minutes to examine for the possible development of acute tolerance. No flumazenil was given in session 4. For a light sedation level, with a mean midazolam plasma concentration of 160 +/- 64 ng/ml, the mean half-life of the equilibration rate constant of flumazenil reversal is 5.0 +/- 2.5 minutes, and the mean effect site concentration causing 50% of Emax is 13.7 +/- 5.8 ng/ml. For a deep level of sedation, with a mean midazolam plasma concentration of 551 +/- 196 ng/ml, the mean half-life of the equilibration rate constant is 3.9 +/- 1.5 minutes, and the mean effect site concentration causing 50% of Emax is 20.6 +/- 6.8 ng/ml. This study provides an estimate of the magnitude of the blood/central nervous system equilibration delay for flumazenil antagonism of midazolam sedation and further defines the usefulness of the electroencephalogram as a measure of midazolam pharmacodynamic effect.

Adult↗
PubMed1997

Possible mechanisms underlying the midazolam-induced relaxation of the noradrenaline-contraction in rabbit mesenteric resistance artery.

1. The mechanisms underlying the midazolam-induced relaxation of the noradrenaline (NA)-contraction were studied by measuring membrane potential, isometric force and intracellular concentration of Ca2+ ([Ca2+]i) in endothelium-denuded muscle strips from the rabbit mesenteric resistance artery. The actions of midazolam were compared with those of nicardipine, an L-type Ca2+-channel blocker. 2. Midazolam (30 and 100 microM) did not modify either the resting membrane potential or the membrane depolarization induced by 10 microM NA. 3. NA (10 microM) produced a phasic, followed by a tonic increase in both [Ca2+]i and force. Midazolam (10-100 microM) did not modify the resting [Ca2+]i, but attenuated the NA-induced phasic and tonic increases in [Ca2+]i and force, in a concentration-dependent manner. In contrast, nicardipine (0.3 microM) attenuated the NA-induced tonic, but not phasic, increases in [Ca2+]i and force. 4. In Ca2+-free solution containing 2 mM EGTA, NA (10 microM) transiently increased [Ca2+]i and force. Midazolam (10-100 microM), but not nicardipine (0.3 microM), attenuated this NA-induced increase in [Ca2+]i and force, in a concentration-dependent manner. However, midazolam (10 and 30 microM), had no effect on the increases in [Ca2+]i and force induced by 10 mM caffeine. 5. In ryanodine-treated strips, which have functionally lost the NA-sensitive Ca2+ storage sites, NA slowly increased [Ca2+]i and force. Nicardipine (0.3 microM) did not modify the resting [Ca2+]i but partly attenuated the NA-induced increases in [Ca2+]i and force. In the presence of nicardipine, midazolam (100 microM) lowered the resting [Ca2+]i and further attenuated the remaining NA-induced increases in [Ca2+]i and force. 6. The [Ca2+]i-force relationship was obtained in ryanodine-treated strips by the application of ascending concentrations of Ca2+ (0.16-2.6 mM) in Ca2+-free solution containing 100 mM K+. NA (10 microM) shifted the [Ca2+]i-force relationship to the left and enhanced the maximum Ca2+-induced force. Under these conditions, whether in the presence or absence of 10 microM NA, midazolam (10 and 30 microM) attenuated the increases in [Ca2+]i and force induced by Ca2+ without changing the [Ca2+]i-force relationship. 7. It was concluded that, in smooth muscle of the rabbit mesenteric resistance artery, midazolam inhibits the NA-induced contraction through its inhibitory action on NA-induced Ca2+ mobilization. Midazolam attenuates NA-induced Ca2+ influx via its inhibition of both nicardipine-sensitive and -insensitive pathways. Furthermore, midazolam attenuates the NA-induced release of Ca2+ from the storage sites. This effect contributes to the midazolam-induced inhibition of the NA-induced phasic contraction.

Animals↗
PubMed1997

I.m. midazolam as premedication produces a concentration-dependent decrease in core temperature in male volunteers.

We tested the hypothesis that premedication with i.m. midazolam decreases core temperature dose-dependently. We studied six male volunteers, in random order, on 3 days: (1) no midazolam administration (control day), (2) midazolam 0.025 mg kg-1 i.m., (3) midazolam 0.075 mg kg-1 i.m. On the first day, subjects were maintained alert during a 30-min control period. On the second and third days, midazolam 0.025 or 0.075 mg kg-1 was administered i.m. Core temperatures were measured at the right tympanic membrane. Four adhesive skin surface probes were fixed on the chest, upper right arm, lateral calf and thigh. Finger tip perfusion was evaluated using forearm minus fingertip and calf minus toe, skin surface temperature gradients. Thirty minutes after midazolam i.m., the level of sedation in the volunteers was assessed. Peripheral venous blood was obtained immediately after the assessment of the level of sedation. Tympanic membrane temperatures after administration of midazolam 0.075 mg kg-1 i.m. were significantly lower than those on the control and midazolam 0.025 mg kg-1 i.m. days at 20 and 30 min. The decreases in tympanic membrane temperatures at 30 min after midazolam i.m. became larger as the volunteers were more deeply sedated. i.m. midazolam produced a concentration-dependent decrease in tympanic membrane temperature at 30 min after midazolam 0.025 and 0.075 mg kg-1 i.m. We conclude that midazolam impaired tonic thermoregulatory vasoconstriction, allowing core-to-peripheral heat redistribution in a dose-dependent manner after i.m. administration.

Adult↗
PubMed2002

Mechanisms of action of midazolam on expression of contextual fear in rats.

BACKGROUND: Midazolam may suppress conditioned fear after an aversive event by disrupting the memory trace formed during conditioning, by altering the emotional part of the aversive event, or by the combination of both effects. The purpose of the present study was to determine whether affective-related processes contribute to the amnesic-like effects of midazolam on aversive events. METHODS: The effects of acute administration of low doses of midazolam (0.37-3 mg kg(-1)) on fear conditioning (association between a neutral context and an aversive stimulus) and on innate anxiety in fearful surroundings were examined in rats. The effect of midazolam on the deleterious consequences of pre-exposure to the context (a non-aversive event) for subsequent fear conditioning was then compared with its effect on fear conditioning. The role of midazolam as an affective context was assessed by performing the testing phase under midazolam. Possible locomotor impairment or long-term effects of midazolam were controlled in additional experiments. RESULTS: Midazolam reduced both contextual fear conditioning and spontaneous fear. The deleterious effect of midazolam on pre-exposure to the context was of the same magnitude as its effect on the acquisition phase of fear conditioning. The effects of midazolam on both pre-exposure to the context and fear conditioning were unchanged when rats received a second injection of midazolam before the retention phase. CONCLUSIONS: Low doses of midazolam that do not impair locomotion suppress conditioned fear to the context by acting on memory processes rather than on affective or anxiolytic processes.

Analysis of Variance↗