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PubMed1997

Integrated pharmacokinetics and pharmacodynamics of Ro 48-6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.

AIMS: This study was performed to investigate the pharmacokinetics and pharmacodynamics of ascending doses of Ro 48-6791, compared with midazolam, in healthy subjects during first administration to man studies. METHODS: The study was double-blind and five-way crossover with treatment on 5 consecutive days (three ascending doses, placebo, fixed midazolam dose) in two sequential groups of five healthy male subjects. Ro 48-6791 was administered as a slow i.v. infusion in doses of 0.1-0.3-1 mg in the first group, and 1-2-3 mg in the second. Midazolam was infused at 0.1 mg kg(-1). The infusions were stopped after 20 min or if sedation became too strong for proper performance of the tests. Consequently, infusion rates (mg min(-1)) differed considerably among doses. Blood samples were collected frequently for pharmacokinetic determinations (two-compartment model). Pharmacodynamics were assessed by recording of saccadic eye movements (saccadic peak velocity) and electroencephalography (beta-power). These parameters were used for pharmacokinetic/pharmacodynamic modelling. RESULTS: Ro 48-6791 and midazolam were both well tolerated. Most clinical events were dose-dependent central depressant effects. The volume of distribution (V(SS)) and plasma clearance of Ro 48-6791 were on average markedly larger than those of midazolam (171 +/- 65 vs 41 +/- 10 l and 2.2 +/- 0.9 vs 0.42 +/- 0.11 l min(-1), respectively). The doses of Ro 48-6791 leading to loss of saccadic eye movements were on average four times lower than that of midazolam. The corresponding predicted effect compartment concentrations differed by a factor of about six. Doses of Ro 48-6791 and midazolam eliciting similar maximum effects had a comparable onset and duration of action for saccadic peak velocity. Midazolam caused a significantly larger (33%, range 17, 55%) increase in beta-power than Ro 48-6791 at the highest administered dose. Ro 48-6792, a metabolite of Ro 48-6791, showed a considerably longer half-life than the parent compound. Although there were no indications of a discernable effect of Ro 48-6792 in the present study, the effects of possible accumulation during prolonged administration should be investigated further. CONCLUSIONS: This first study with Ro 48-6791 in humans has shown that this benzodiazepine is approximately four to six times as potent as midazolam, but has a comparable onset and duration of action.

Adjuvants, Anesthesia↗
PubMed2000

Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1'-hydroxylation.

AIMS: To characterize the effect of an oral contraceptive (OC) containing ethinylestradiol and gestodene on the activity of CYP3A4 in vivo as measured by the 1'-hydroxylation of midazolam. METHODS: In this randomised, double-blind, cross-over trial nine healthy female subjects received either a combined OC (30 microg ethinylestradiol and 75 microg gestodene) or placebo once daily for 10 days. On day 10, a single 7.5 mg dose of midazolam was given orally. Plasma concentrations of midazolam and 1'-hydroxymidazolam were determined up to 24 h and the effects of midazolam were measured with three psychomotor tests up to 8 h. RESULTS: The combined OC increased the mean AUC of midazolam by 21% (95% CI 2% to 40%; P = 0.03) and decreased that of 1'-hydroxymidazolam by 25% (95% CI 10% to 41%; P = 0.01), compared with placebo. The metabolic ratio (AUC of 1'-hydroxymidazolam/AUC of midazolam) was 36% smaller (95% CI 19% to 53%; P = 0.01) in the OC phase than in the placebo phase. There were no significant differences in the Cmax, tmax, t(1/2) or effects of midazolam between the phases. CONCLUSIONS: A combined OC preparation caused a modest reduction in the activity of CYP3A4, as measured by the 1'-hydroxylation of midazolam, and slightly increased the AUC of oral midazolam. This study suggests that, at the doses used, ethinylestradiol and gestodene have a relatively small effect on CYP3A4 activity in vivo.

Adult↗
PubMed2002

Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers.

AIMS: To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. METHODS: Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. beta-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. RESULTS: Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (+/-s.d.) peak plasma concentration of midazolam of 71 (+/-25 ng ml-1) was reached after 14 (+/-5 min). Mean bioavailability following intranasal administration was 0.83+/-0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11+/-0.25 l kg-1, mean systemic clearance 16.1+/-4.1 ml min-1 kg-1 and harmonic mean initial and terminal half lives 8.4+/-2.4 and 79+/-30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration. CONCLUSIONS: In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.

Administration, Intranasal↗
PubMed2002

Intestinal first pass metabolism of midazolam in liver cirrhosis --effect of grapefruit juice.

AIMS: Grapefruit juice inhibits CYP3A4 in the intestinal wall leading to a reduced intestinal first pass metabolism and thereby an increased oral bioavailability of certain drugs. For example, it has been shown that the oral bioavailability of midazolam, a CYP3A4 substrate, increased by 52% in healthy subjects after ingestion of grapefruit juice. However, this interaction has not been studied in patients with impaired liver function. Accordingly, the effect of grapefruit juice on the AUC of midazolam and the metabolite alpha-hydroxymidazolam was studied in patients with cirrhosis of the liver. METHODS: An open randomized two-way crossover study was performed. Ten patients (3 females, 7 males) with liver cirrhosis based on biopsy or clinical criteria participated. Six patients had a Child-Pugh score of A, one B and three C. Tap water (200 ml) or grapefruit juice were consumed 60 and 15 min before midazolam (15 mg) was administered orally. Plasma samples were analysed for midazolam and alpha-hydroxymidazolam. RESULTS: Grapefruit juice increased the AUC of midazolam by 106% (16, 197%) (mean (95% confidence interval)) and the AUC of the metabolite alpha-hydroxymidazolam decreased to 25% (12, 37%) (P<0.05 for both). The ratio of the AUCs of the metabolite alpha-hydroxymidazolam to midazolam decreased from 0.77 (0.46, 1.07) to 0.11 (0.05, 0.19) (P<0.05). t(1/2) remained unaltered for both drug and metabolite. Midazolam C(max), t(max), and alpha-hydroxymidazolam t(max) increased, but these changes were not statistically significant, whereas C(max) of the metabolite decreased to 30% (14, 47%) (P<0.05). CONCLUSIONS: A marked interaction between oral midazolam and grapefruit juice was found and the data are consistent with a reduced first-pass metabolism of midazolam. This is likely to occur at the intestinal wall inhibition of CYP3A4 activity by grapefruit juice. These results indicate that patients with liver cirrhosis are more dependent on the intestine for metabolism of CYP3A4 substrates than subjects with normal liver function.

Adult↗
PubMed2003

Oral high-dose midazolam premedication for infants and children undergoing cardiovascular surgery.

BACKGROUND: The purpose of this study was to determine whether oral midazolam 1.5 mg x kg(-1) is a safe and effective alternative to standard-dose midazolam (0.5-1.0 mg x kg(-1)) premedication for infants and children with congenital heart disease. METHODS: A total of 193 infants and children (4 months to 2 years) undergoing cardiovascular surgery were studied. Each patient received 0.5, 1.0, or 1.5 mg x kg(-1) of oral midazolam. The level of sedation was assessed with a 5-point scale and vital signs were measured including blood pressure (BP), heart rate (HR) and oxyhaemoglobin saturation (SpO2) before and after the medication. RESULTS: Infants and children premedicated with oral midazolam 1.5 mg x kg(-1) were better sedated than those with standard-dose midazolam: 4% of infants and children given 1.5 mg x kg(-1) of midazolam became agitated compared with 14% given 1.0 mg x kg(-1) and 26% in those given 0.5 mg x kg(-1). Ninety percentage of infants and children given 1.5 mg x kg(-1) of midazolam achieved satisfactory sedation (calm, drowsy, or asleep) in 30 min, whereas 68% in those given 1.0 mg x kg(-1) and 35% in those given 0.5 mg x kg(-1). Midazolam 1.5 mg x kg(-1) did not cause any statistically significant decrease in BP, HR, or SpO2, although eight infants and children showed > or =20% drop in systolic BP and six infants and children showed >5% drop in SpO2. No 'spelling attacks', seizure-like activity, apnoea, nor laryngospasm were observed in any infants and children during and after the medication. CONCLUSIONS: Oral midazolam 1.5 mg x kg(-1) is excellent for preanaesthetic medication for infants and children undergoing cardiovascular surgery.

Administration, Oral↗
PubMed1999

Propofol decreases the clearance of midazolam by inhibiting CYP3A4: an in vivo and in vitro study.

OBJECTIVE: To examine the effect of propofol on the pharmacokinetics of midazolam in vivo and to elucidate the mechanism of the pharmacokinetic changes of midazolam by propofol with the use of human liver microsomes and recombinant CYP3A4. METHODS: In an in vivo, double-blind randomized study, 24 patients received 0.2 mg/kg midazolam and either 2 mg/kg propofol (propofol group) or placebo (placebo group) for induction of anesthesia. In the propofol group, continuous infusion of propofol at 9 mg/kg/h was started immediately after the bolus infusion of propofol and was maintained for an hour. In the placebo group the same dose of soybean emulsion as a placebo was given and infused intravenously for an hour instead of propofol. In an in vitro study the effect of propofol on the metabolism of midazolam was studied with human liver microsomes and recombinant CYP3A4. RESULTS: In the propofol group the mean clearance of midazolam was decreased by 37% (P = .005) and the mean elimination half-life was prolonged by 61% (P = .04) compared with the placebo group. The mean plasma concentrations of 1'-hydroxymidazolam were lower in the propofol group than in the placebo group at 5, 10, 15, 20, and 30 minutes after midazolam was administered (P < .05). The mean (+/-SD) Michaelis-Menten constant for midazolam 1'-hydroxylation by human liver microsomes was 5.6 +/- 3.3 micromol/L. The formation of 1'-hydroxymidazolam was competitively inhibited by propofol, and the mean inhibition constant was 56.7 +/- 16.6 micromol/L. The mean Michaelis-Menten constant and mean inhibition constant values for midazolam 1'-hydroxylation by recombinant CYP3A4 were 4.0 micromol/L and 61.0 micromol/L, respectively, consistent with the mean values obtained from human liver microsomes. CONCLUSION: Propofol decreases the clearance of midazolam, and the possible mechanism is the competitive inhibition of hepatic CYP3A4.

Adult↗
PubMed2000

[Sympathoadrenergic, hemodynamic and stress response during coinduction with propofol and midazolam].

OBJECTIVE: This study was undertaken to investigate simultaneously the influence of coinduction with propofol and midazolam on sympathoadrenergic and hemodynamic reactions and stress response during the extended induction period of TIVA. METHODS: 2 x 20 patients over the 60th year of life with major visceral surgery were investigated in a prospective randomized design. All patients received about 0.1 mg/kg BW midazolam for oral premedication. In the midazolam-group, induction of TIVA was undertaken with 0.05 mg/kg BW midazolam, 2.5 micrograms/kg BW fentanyl and 1.0 mg/kg BW propofol (1 min later). Controls received 2.5 micrograms/kg BW fentanyl and 2.0 mg/kg BW propofol. After muscle relaxation with 0.1 mg/kg BW vecuronium, TIVA was conducted in both groups with 8-5 mg/kg BW/h propofol and bolus injections of fentanyl with respect to clinical demands. Beyond consumption of anesthetics and recovery, sympathoadrenergic and hemodynamic reactions and SEF90 were investigated at 6 time points before induction of anesthesia and at skin incision. Plasma levels of ADH, ACTH and cortisol were measured twice before induction and at skin incision. RESULTS: Biometric data of both groups were comparable, and mean age was over 65 years. In the midazolam-group, co-induction with a mean dosage of 3.8 mg midazolam halved the induction dose of propofol and reduced the propofol demand during the following course of anesthesia as well, achieving a significant over all reduction of 200 mg propofol (p = 0.04). With respect to recovery from anesthesia more than 90 min later, no significant differences were found. Plasma concentrations of noradrenaline and adrenaline dropped significantly in both groups (p < 0.0001), as well as mean arterial pressure and heart rate (Fig. 1 and 2). For ADH, ACTH, cortisol and SEF90, no statistical differences were observed. Plasma-concentrations of midazolam were significantly higher in the midazolam-group. CONCLUSION: In elderly patients, co-induction with 0.05 mg/kg BW midazolam halved the induction dose of propofol and led to a further dose reduction with maintained hypnotic potency. However, the halvage of propofol induction dose had no effect on the reduction of the sympathoadrenergic tone with decrease of blood pressure and heart rate. The overall moderation of the stress response was comparable as well. Thus, both induction regimens investigated in this study cannot be recommended in patients with severe hemodynamic disorders like hemorrhagic or cardiac shock. The propofol reduction should be primarily considered under economic aspects.

Aged↗
PubMed2002

The effect of midazolam on the normal sphincter of Oddi: a controlled study.

BACKGROUND AND STUDY AIMS: Midazolam HCl (Versed) is often used for intravenous conscious sedation in endoscopic retrograde cholangiopancreatography (ERCP) and is increasingly used in endoscopic sphincter of Oddi (SO) manometry. The effect of medications on SO motility should be fully characterized if they are to be used during SO manometry. There has been controversy as to whether midazolam influences SO motility. The aim of this study was to determine the effect of midazolam on the normal SO. PATIENTS AND METHODS: The study population consisted of 60 patients presenting with recurrent abdominal pain who were found to have SO basal pressure of less than 40 mmHg on SO manometry. ERCP was performed in the standard fashion using a pneumohydraulic capillary perfused triple-lumen catheter system in a stationary pull-through method from the pancreatic and common bile ducts. In the test group 30 patients received 2 mg midazolam intravenously while the 30 patients in the control group received intravenous saline. SO manometry was performed, with recording of the basal pressure, phasic pressure, phasic amplitude, phasic frequency and ductal pressure before and 3 min after the intravenous infusion. The changes in basal, phasic and duct pressure as well as phasic frequency before and after the administration of saline and midazolam were compared. RESULTS: Midazolam causes a small but statistically significant reduction in basal and peak SO pressure (4 and 19 mmHg respectively), compared with saline. Diagnostic concordance (normal vs. abnormal) between the basal sphincter pressure before and after midazolam was seen in 100 % of patients. Midazolam does not significantly affect phasic amplitude, phasic frequency or duct pressure. CONCLUSIONS: Midazolam does not have a clinically significant influence on the accuracy of SO manometry in identifying normal sphincteric motility.

Abdominal Pain↗
PubMed1993

[Low-dose midazolam reduces the alfentanil demand in elderly but not in young patients during extracorporeal shock wave lithotripsy].

To evaluate whether midazolam has analgesic properties in humans after intravenous injection we studied the influence of a subhypnotic dose of midazolam (50 micrograms/kg) on the cumulative alfentanil consumption in 53 patients during extracorporeal shock wave lithotripsy (ESWL) using a patient-controlled analgesia system (PCAS). In a randomised double blind fashion all patients received either midazolam or an equal volume of saline (placebo) prior to ESWL. Heart rate and arterial blood pressure were measured before and during ESWL. Alfentanil consumption was assessed 20 minutes after injection of midazolam or placebo, respectively. All patients received oxygen via face mask. In patients older than 60 years (median: 70 years, range: 61-88 years) pretreatment with midazolam resulted in a significantly lower cumulative alfentanil consumption (0.41 vs 0.97 mg; p = 0.027) compared with patients younger than 60 years after midazolam pretreatment (0.84 vs 0.71 mg; p = 0.27). Mean arterial pressure also was significantly lower in the former compared with the latter group, while heart rate remained unchanged. In contrast, in patients younger than 60 years (median: 47 years, range: 24-56 years) no significant differences were observed between the midazolam and the placebo group. Thus, low dose intravenous midazolam pretreatment led to a significant decrease of alfentanil consumption in patients beyond 60 years of age. We conclude that subhypnotic doses of midazolam are capable of reducing alfentanil demand in elderly but not in younger patients during ESWL.

Adult↗
PubMed2001

CYP3A activity in European American and Japanese men using midazolam as an in vivo probe.

OBJECTIVE: To investigate putative differences in CYP3A activity between European American and Japanese subjects using midazolam as an in vivo probe. METHODS: Midazolam was administered orally (2 mg) to 22 young healthy Japanese men and, on a separate occasion, to 19 of these by the intravenous route (1 mg). The disposition of the drug and its 1'-hydroxy metabolite were determined and compared with data collected in a similar fashion in 20 young healthy European American men. RESULTS: Plasma concentrations of midazolam, especially those attained soon after drug administration, were higher after intravenous injection in Japanese subjects than those in European American men. This observation was associated with smaller initial (2.5-fold) and steady-state (1.8-fold) volumes of distribution for the drug; normalization for body weight only modestly reduced these differences. The systemic clearance value of midazolam was 25% lower (P < .03) in Japanese subjects, but this difference was not apparent after accounting for the smaller body weights of that group. No statistical differences were noted in the elimination half-life (t 1/2) of midazolam between European American and Japanese subjects. Much greater interindividual variability was observed after oral administration compared with intravenous administration, but significant differences were not found between the 2 groups with respect to the maximum midazolam plasma level or its oral clearance. Absolute oral bioavailability and its associated gastrointestinal and hepatic extraction ratios also showed no statistically significant interracial differences. CONCLUSIONS: On average, hepatic CYP3A, as measured by the metabolism of midazolam, is lower in young healthy Japanese men compared with similar European Americans. However, there is considerable interindividual variability, and body size appears to be an important determinant. After oral administration, even greater variability in the plasma level-time profile of midazolam is present, and no statistically significant or clinically important interracial/ethnic difference is present. Possibly because of smaller body mass and differences in body composition, midazolam has a smaller distribution volume(s) in Japanese men than in European American men that might be an important factor when drugs are administered intravenously.

Administration, Oral↗
PubMed2002

Central-nervous side effects of midazolam during transesophageal echocardiography.

BACKGROUND: Midazolam is a broadly used drug that can enhance tolerance to transesophageal echocardiography (TEE) in patients with cardiac conditions. Adverse reactions to midazolam have been described previously. We describe central-nervous side effects in 6 of 104 consecutive patients. METHODS: One hundred four patients undergoing TEE-diagnostic procedure were investigated. TEE was performed using a SSA 360 Power Vision ultrasound unit (Toshiba, Tokyo, Japan) and a 5- to 6-MHz probe. Indication for TEE was evaluation of cardiac valves (6), search for cardiac embolism (23), patent foramen ovale or atrial septum defect (20), left ventricular dysfunction (11), aortic dissection (7), and other (37). Midazolam and, if necessary, the benzodiazepine antagonist flumazenil (0.25-0.5 mg) were administered intravenously. RESULTS: The mean cumulative dose of midazolam administered in small fractions was 4.8 +/- 2 mg. In 6 of 104 patients (5.7%) clinically significant adverse effects to midazolam occurred. The reactions were aggressiveness, euphoria, depression, and intense hiccups (singultus) despite low doses of midazolam. The severest forms of these adverse effects to midazolam could be successfully treated with intravenous infusion of flumazenil (0.25-0.5 mg intravenously). CONCLUSION: Adverse effects including aggressive, euphoric, or depressive behavior can occur in a significant proportion (6%) of patients with cardiac conditions undergoing TEE after intravenous administration of midazolam. The administration of the benzodiazepine antagonist flumazenil can reverse the adverse effects to midazolam successfully.

Adult↗
PubMed1993

Plasma concentrations of midazolam after i.v., nasal or rectal administration in children.

Midazolam is used frequently for premedication in children, preferably by non-parenteral administration. We have compared plasma concentrations of midazolam after nasal, rectal and i.v. administration in 45 children (aged 2-9 yr; weight 10-30 kg) undergoing minor urological surgery. General anaesthesia consisted of spontaneous respiration of halothane and nitrous oxide in oxygen via a face mask. After administration of atropine and fentanyl i.v., children were allocated randomly to receive midazolam 0.2 mg kg-1 by the nasal, rectal or i.v. route. In the nasal group, children received 50% of the dose of midazolam in each nostril. In the rectal group, midazolam was given rectally via a cannula. Venous blood samples were obtained before and up to 360 min after administration of the drug. Plasma concentrations of midazolam were measured by gas chromatography and electron capture detection. After nasal and rectal administration, midazolam Cmax was 182 (SD 57) ng ml-1 within 12.6 (5.9) min, and 48 (16) ng ml-1 within 12.1 (6.4) min, respectively. Rectal administration resulted in smaller plasma concentrations. In the nasal group, a plasma concentration of midazolam 100 ng ml-1 occurred at about 6 min. After 45 min, the concentration curves after i.v. and nasal midazolam were similar.

Administration, Intranasal↗
PubMed1998

Interaction of a subanaesthetic concentration of isoflurane with midazolam: effects on responsiveness, learning and memory.

There are situations in which "light" anaesthesia combined with neuromuscular block is the only anaesthetic regimen that can be tolerated safely by the patient. Benzodiazepines have hypnotic and specific amnesic effects. Therefore, we have examined the interaction of midazolam with a subanaesthetic dose of isoflurane (0.2% end-expired concentration) in 28 healthy volunteers. Thereafter, 15 subjects received midazolam 0.03 mg kg-1 i.v. and 13 subjects received midazolam 0.06 mg kg-1 in a random, double-blind manner. Word lists were administered and response to commands was tested before and after administration of midazolam. After 1 h of recovery, memory for word lists was tested by word completion, free recall and forced choice recognition tasks. After administration of midazolam, recall and, to a lesser degree, implicit memory were absent. Recognition was also absent after administration of midazolam 0.06 mg kg-1 and at the 3-min and 15-min assessments after administration of midazolam 0.03 mg kg-1. Responsiveness was more frequent with midazolam 0.03 mg kg-1 than with 0.06 mg kg-1 and increased over time. We conclude that a larger dose of midazolam or isoflurane, or both, may be necessary to abolish responsiveness.

Adult↗
PubMed2003

Randomized, controlled, cross-over clinical trial comparing intravenous midazolam sedation with nitrous oxide sedation in children undergoing dental extractions.

BACKGROUND: The use of benzodiazepines for paediatric dental sedation has received limited attention with regard to research into clinical effectiveness. A study was therefore designed to investigate the use of midazolam, for i.v. sedation in paediatric dental patients. METHOD: The aim of the study was to assess the effectiveness of i.v. midazolam in a randomized, controlled, cross-over trial. Children aged 12-16 yr (ASA I and II), requiring two appointments for equivalent but contralateral dental extractions for orthodontic purposes, were recruited. Conscious sedation with either i.v. midazolam titrated at 0.5 mg x min(-1), to a maximum of 5 mg, or nitrous oxide/oxygen titrated to 30%/70% inhalation sedation was used at the first visit, the alternative being used at the second visit. Vital signs including blood pressure, arterial oxygen saturation and ventilatory frequency, as well as sedation levels and behavioural scores, were recorded every 2 min. RESULTS: Forty patients, mean age 13.2 yr (range 12-16 yr), participated in the trial. A mean dose of midazolam 2.8 mg was administered in the test group. The median time to the maximum level of sedation was 8 min for midazolam compared with 6 min for nitrous oxide (P<0.001). Vital signs for both treatments were comparable and within acceptable clinical limits and communication with the patient was maintained at all times. The median (range) lowest arterial oxygen saturation level recorded for midazolam was 97 (91-99)% compared with 97 (92-100)% for nitrous oxide. The mean (range) recovery time for midazolam was 51.6 (39-65) min and 23.3 (20-34) min for nitrous oxide (P<0.0001). Fifty-one per cent said they preferred i.v. midazolam, 38% preferred nitrous oxide, and 11% had no preference. CONCLUSION: I.V. midazolam sedation (0.5 mg x min(-1) to a maximum of 5 mg) appears to be as effective as nitrous oxide sedation in 12-16-yr-old healthy paediatric dental patients.

Adolescent↗
PubMed2004

Double-blind randomized controlled trial to determine extent of amnesia with midazolam given immediately before general anaesthesia.

BACKGROUND: Anterograde, but not retrograde, amnesia has been demonstrated following midazolam administration. However, there have been no studies investigating whether or not immediate retrograde amnesia can be produced with midazolam. METHODS: After ethics committee approval and consent, 40 adult patients undergoing surgery and general anaesthesia were randomly allocated to one of four groups: midazolam 2 mg, midazolam 5 mg, midazolam 10 mg or control (normal saline). Measurements were made from 12 min prior to induction of anaesthesia, and the study drug was administered 8 min prior to induction of anaesthesia. Midazolam effects were measured using visual recognition of posters, recall of specific events, bispectral index (BIS) and sedation visual analogue score. RESULTS: Recognition and recall rates were similar between groups up until the time of study drug administration, with no evidence of retrograde amnesia (all P>0.3). There was a dose-dependent deterioration in visual recall (P=0.002), event recollection (P<0.001), BIS (P<0.001) and sedation score (P<0.001) following i.v. midazolam when compared with control. CONCLUSIONS: We found no evidence that i.v. midazolam 2-10 mg produces immediate retrograde amnesia. Midazolam causes anterograde amnesia in a dose-responsive manner.

Adult↗
PubMed1995

Intravenous midazolam suppresses noxiously evoked activity of spinal wide dynamic range neurons in cats.

The effects of intravenously (i.v.) administered midazolam on noxiously evoked activity of spinal wide dynamic range (WDR) neurons were investigated in decerebrate, spinal-cord-transected cats. Extracellular, single-unit recordings were measured during stimulation by pinching the receptive field on the hind paw and the effect of midazolam at doses of 0.25, 0.5, 1, 2, and 4 mg/kg were measured. Two series of experiments were performed to characterize the analgesic effects of midazolam. In the first, dose-response experiments (n = 59) demonstrated a dose-dependent suppression of the noxiously evoked activity of spinal WDR neurons after midazolam administration. This effect of midazolam was maximal at a dose of 1 mg/kg i.v.. The second series of experiments (n = 14) demonstrated that a benzodiazepine antagonist, flumazenil (n = 8), promptly reversed the effect of midazolam, while an opioid antagonist, naloxone (n = 6), had no effect on the effect of midazolam. The present study demonstrates that i.v. administered midazolam suppresses noxiously evoked activity of spinal WDR neurons that is reversible by a benzodiazepine antagonist. This is consistent with an analgesic action of midazolam.

Animals↗
PubMed1998

The effects of age and gender on the optimal premedication dose of intramuscular midazolam.

UNLABELLED: We conducted a double-blind study on the effects of age and gender on the optimal premedication dose of i.m. midazolam. We randomly divided 100 male and 100 female patients in each of three age groups: A = 20-39 yr, B = 40-59 yr, and C = 60-79 yr (total 600 patients) into five groups according to midazolam dosage: 0.04, 0.06, 0.08, 0.10, and 0.12 mg/kg. Midazolam was injected i.m. with atropine 0.01 mg/kg 15 min before the induction of anesthesia. Blood pressure (BP), heart rate, respiratory rate, oxygen saturation (SpO2), sedation level, tongue root depression, eyelash reflex, and anterograde amnesia were monitored. There were no significant differences between male and female patients in any variables in any age. Decrease of SpO2 and loss of eyelash reflex were seen with midazolam 0.10 mg/kg in Group A, and with 0.08 mg/kg in Group B. In Group C, decreases in BP and SpO2, loss of eyelash reflex, and depression of the tongue root were observed with midazolam 0.06 mg/kg. In conclusion, the optimal doses of i.m. midazolam administered 15 min before the induction of anesthesia in male or female patients were 0.08, 0.06, and 0.04 mg/kg for Groups A, B, and C, respectively. IMPLICATIONS: Midazolam is the most widely used preoperative anxiolytic drug. Our purpose was to evaluate the optimal dose of i.m. midazolam that would maximize the desired effects and minimize the side effects in a common clinical setting. Results indicate that age, but not gender, should affect the i.m. midazolam dose selected for premedication.

Adult↗
PubMed1999

The effects of midazolam on pure tone audiometry, speech audiometry, and audiological reaction times in human volunteers.

UNLABELLED: Auditory evoked potentials are effected by benzodiazepines, as is cortical processing of auditory stimuli. The effect of benzodiazepines on auditory sensitivity has not, however, been studied. We designed the present study to investigate the effect of sedative doses of midazolam on pure tone and speech audiometry and on audiological reaction times in healthy volunteers. Thirty volunteers underwent baseline audiological assessment for pure tones and speech and had their audiological reaction times measured at 10 and 50 dB above their threshold hearing level at a frequency of 1 kHz. Subjects were then randomly assigned to one of two groups. Group A (n = 15) received midazolam (0.04 mg/kg) IV, and Group B (n = 15) received a similar volume of placebo IV. The audiological tests were repeated 5 min later, and performance was compared with baseline data. Scheffé post hoc tests were used to assess the significance of changes in each group. There was no pre- to posttest change in audiological performance in either the placebo group (P = 0.194) or the midazolam group (P = 0.957). Speech audiometry performance was likewise unaffected by midazolam (P = 0.154). Reaction time at the 10-dB and 50-dB sensation levels were both significantly prolonged after midazolam administration (P = 0.023 and P = 0.012, respectively). In this study, we demonstrate that sedation with midazolam (0.04 mg/kg) does not alter pure tone or speech audiometric thresholds, but it does significantly delay the reaction time to auditory stimuli. Medical practitioners should advise midazolam-sedated patients of their impaired reaction to auditory warning signals (e.g., traffic and car horns) as part of the day-ward discharge recommendations. IMPLICATIONS: In this study, we demonstrate that sedation of healthy volunteers with the benzodiazepine midazolam, in the common clinical dosage, does not affect their hearing capability as measured by pure tone and speech audiometry. However, one's ability to react to auditory signals is impaired after midazolam, which may have implications for patients after day-case procedures.

Adult↗