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PubMed2004

Kinetics and EEG effects of midazolam during and after 1-minute, 1-hour, and 3-hour intravenous infusions.

The objective of this study was to evaluate the kinetics and dynamics of midazolam when administered by three different infusion schemes, using electroencephalography to measure pharmacodynamic effects. In a three-way crossover study, 8 volunteers received midazolam (0.1 mg/kg) by constant-rate intravenous infusion. The durations of midazolam infusions for the three trials were 1 minute, 1 hour, and 3 hours. Plasma midazolam concentrations and electroencephalographic (EEG) activity in the 13- to 30-Hz range were monitored for 24 hours. Based on separate analysis of each subject-trial, mean values for volume of distribution and distribution or elimination half-life did not significantly vary. Central compartment volume and clearance differed among the three midazolam infusion trials; however, the magnitude of change was small. EEG activity in the 13- to 30-Hz range significantly increased for all three midazolam infusion trials. Plots of midazolam plasma concentration versus pharmacodynamic EEG effect for the 1-hour and 3-hour infusion trials did not reveal evidence of either counterclockwise or clockwise hysteresis. Plots from the 1-minute infusion trial demonstrated counterclockwise hysteresis, consistent with an equilibration effect-site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic EEG effect via the sigmoid E(max) model. Analysis of all three infusion trials together yielded the following mean estimates: maximum EEG effect, 16.3% over baseline; 50% maximum effective concentration, 31 ng/mL; and an apparent rate constant for drug disappearance from the effect compartment which approached infinity. Despite the delay in effect onset during the 1-minute midazolam infusion, midazolam infusions in duration of up to 3 hours produce CNS sedation without evidence of tolerance.

Adult↗
PubMed2005

Status epilepticus: clinical analysis of a treatment protocol based on midazolam and phenytoin.

The efficacy of a combination of midazolam and phenytoin in treating generalized convulsive status epilepticus in children was studied retrospectively. The patient group comprised all patients admitted for generalized convulsive status epilepticus to the pediatric intensive care unit over 7 years. Patients treated according to the protocol were included (N = 122). These patients were treated with the following regimen; each subsequent step was taken if clinical evidence of epileptic activity persisted: midazolam 0.5 mg/kg rectally or 0.1 mg/kg intravenously. After 10 minutes: midazolam 0.1 mg/kg intravenously. After 10 minutes: phenytoin 20 mg/kg intravenously in 20 minutes. After phenytoin load: midazolam 0.2 mg/kg intravenously followed by midazolam 0.1 mg/kg/hour continuously, increased by 0.1 mg/kg/hour every 10 minutes to maximum 1 mg/kg/hour. Phenobarbital 20 mg/kg intravenously or pentobarbital 2 to 5 mg/kg intravenous load, 1 to 2 mg/kg/hour continuously intravenously. Patients who received initial rectal diazepam were included. Patients were categorized according to the cause of generalized convulsive status epilepticus. These categories were then related to the level of antiepileptic therapy needed. Patients' ages ranged from 0.5 to 197.4 months. The cause of generalized convulsive status epilepticus was idiopathic or febrile convulsions in two thirds of cases. Most (89%) patients were managed on midazolam and phenytoin. Generalized convulsive status epilepticus was terminated with midazolam alone in 58 patients, with the addition of phenytoin in 19 patients and with continuous midazolam in 32 patients. Thirteen patients needed additional barbiturates. The relationship between the level of antiepileptic therapy and etiology was not significant. Fifty-two patients needed artificial ventilation. Seven patients died; no deaths were directly attributable to generalized convulsive status epilepticus itself. With the use of the proposed protocol, combining midazolam and phenytoin, 89% of the cases of generalized convulsive status epilepticus could be successfully managed.

Adolescent↗
PubMed1999

Dose-dependent intestinal and hepatic first-pass metabolism of midazolam, a cytochrome P450 3A substrate with differently modulated enzyme activity in rats.

The dose-dependent first-pass metabolism of midazolam, a cytochrome P450 (CYP) 3A substrate, was separately estimated in the intestine and liver after administration into a jejunal loop of rats with differently modulated enzyme activity. Modulation of CYP3A enzyme activity of Sprague-Dawley rats was performed by pretreating the rats with inducers such as dexamethasone or by co-administering ketoconazole (an inhibitor) with midazolam. Bioavailabilities of midazolam administered into the jejunal loop at a dose of 10 micromol were 12% in untreated (control) rats, and 2% in dexamethasone-pretreated rats. Co-administered ketoconazole (2 micromol) significantly increased the bioavailability to 53% and 7%, respectively, in these rats. The intestinal first-pass metabolism of midazolam administered into the jejunal loop at a dose of 50 nmol in untreated and dexamethasone-pretreated rats, estimated by the mesenteric blood-collecting method in-situ, was 25% and 49% of absorbed amount, respectively. The intestinal first-pass metabolism of midazolam was reduced when ketoconazole (0.5 micromol) was co-administered or when the dose of midazolam was increased to 0.5 micrommol in these rats. Assuming that the contribution of intestinal first-pass metabolism could be negligible when midazolam was administered at a much higher dose of 10 micromol, the estimated hepatic first-pass metabolism of midazolam at a dose of 10 micromol in untreated rats, dexamethasone-pretreated rats, untreated rats given ketoconazole, and dexamethasone-pretreated rats given ketoconazole was, respectively, 86, 97, 46, and 92% of the amounts absorbed. In conclusion, the dose-dependent intestinal first-pass metabolism and the hepatic first-pass metabolism of midazolam in rats with differently modulated CYP3A activities was quantitatively estimated by in-vivo and in-situ absorption studies.

Animals↗
PubMed1992

Comparison of etomidate, ketamine, midazolam, propofol, and thiopental on function and metabolism of isolated hearts.

The authors examined direct myocardial and coronary vascular responses to the anesthetic induction agents etomidate, ketamine, midazolam, propofol, and thiopental and compared their effects on attenuating autoregulation of coronary flow as assessed by changes in oxygen supply/demand relationships. Spontaneous heart rate, atrioventricular conduction time during atrial pacing, left ventricular pressure (LVP), coronary flow (CF), percent oxygen extraction, oxygen delivery, and myocardial oxygen consumption (MVo2) were examined in 55 isolated guinea pig hearts divided into five groups of 11 each. Hearts were perfused at constant pressure with one of the drugs administered at steady-state concentrations increasing from 0.5 microM to 1 mM. Adenosine was given to test maximal CF. At concentrations below 10 microM no significant changes were observed; beyond 50 microM for midazolam, etomidate, and propofol, and 100 microM for thiopental and ketamine, each agent caused progressive but differential decreases in heart rate, atrioventricular conduction time (leading to atrioventricular dissociation), LVP, +dLVP/dtmax, percent oxygen extraction, and MVo2. The concentrations (microM) at which +dLVP/dtmax was reduced by 50% were as follows: etomidate, 82 +/- 2 (mean +/- SEM); propofol, 91 +/- 4; midazolam, 105 +/- 8; thiopental, 156 +/- 11; and ketamine, 323 +/- 7; the rank order of potency was etomidate = propofol = midazolam greater than thiopental greater than ketamine; results were similar for LVP. At the 100 microM concentration, CF was decreased 11% +/- 2% by ketamine and 5% +/- 3% by thiopental but was increased 17% +/- 6% by etomidate, 21% +/- 5% by midazolam, and near maximally to 57% +/- 10% by propofol; MVo2 was decreased 8% +/- 4% by thiopental, 10% +/- 5% by ketamine, 19% +/- 5% by midazolam, 29% +/- 7% by etomidate, and 37% +/- 5% by propofol; oxygen delivery/MVo2 was unchanged by thiopental and ketamine but was increased 62% +/- 7% by midazolam, 71% +/- 9% by etomidate, and 150% +/- 15% by propofol. Between 100 microM and 1 mM, thiopental and ketamine did not increase CF but decreased MVo2 and percent oxygen extraction, whereas propofol maximally increased CF and decreased MVo2 and midazolam and etomidate had intermediate effects. These results indicate that on a molar basis, propofol, and less so midazolam and etomidate, depress cardiac function moderately more than thiopental and ketamine, and that propofol markedly attenuates autoregulation by causing coronary vasodilation. With doses used to induce anesthesia, propofol and thiopental appear to depress cardiac function more than ketamine or etomidate.

Adenosine↗
PubMed2003

Sequential use of midazolam and propofol for long-term sedation in postoperative mechanically ventilated patients.

UNLABELLED: Acute withdrawal syndromes, including agitation and a long weaning time, are common adverse effects after long-term sedation with midazolam. We performed this study to determine whether the sequential use of midazolam and propofol could reduce adverse effects as compared with midazolam alone. We studied 26 patients receiving mechanical ventilation for three or more days after surgery. Patients were randomly assigned to two groups. In Group M, patients were sedated with midazolam alone. In Group M-P, midazolam was switched to propofol approximately 24 h before the expected stopping of sedation. The level of sedation was maintained at 4 or 5 on the Ramsay sedation scale. The sedation agitation scale was evaluated for 24 h after extubation. The recovery time from stopping of sedation to extubation was significantly shorter in Group M-P (1.3 +/- 0.4 h) compared with Group M (4.0 +/- 2.4 h). The incidence of agitation in Group M-P (8%) was significantly less frequent than that in Group M (54%). The results indicate that sequential use of midazolam and propofol for long-term sedation could reduce the incidence of agitation compared with midazolam alone. IMPLICATIONS: Our study indicates that sequential use of midazolam and propofol could reduce the incidence of agitation compared with midazolam alone.

Analgesics, Opioid↗
PubMed2005

Spinal cord blood flow change by intravenous midazolam during isoflurane anesthesia.

We investigated the effects of IV midazolam on spinal cord blood flow in 32 cats anesthetized with isoflurane. Cats underwent laminectomy, and the lumbar spinal cord was exposed. A platinum electrode was inserted stereotaxically into the spinal cord to a depth of 1 mm-2 mm lateral to midline at L2. Arterial blood pressure, heart rate, and spinal cord blood flow (using the hydrogen clearance method) were measured before and at 5, 15, 30, 60, 90, and 120 min after an IV bolus of midazolam (0, 1, 2, or 4 mg/kg in saline 5 mL; n = 8 cats per dose). Arterial blood pressure was not affected by 0 or 1 mg/kg of midazolam but was decreased for 30 min by 2 or 4 mg/kg of midazolam. Heart rate did not change. Spinal cord blood flow was increased for 90 min by midazolam 1 mg/kg and for 15 min by midazolam 2 mg/kg but was not changed by midazolam 4 mg/kg. In conclusion, 1 mg/kg of midazolam increased feline spinal cord blood flow without changing arterial blood pressure. In contrast, a larger dose of midazolam (4 mg/kg) did not change spinal cord blood flow but substantially decreased arterial blood pressure during isoflurane anesthesia.

Adjuvants, Anesthesia↗
PubMed1995

Premedication with oral midazolam for voiding cystourethrography in children: safety and efficacy.

OBJECTIVE: Midazolam is a relatively short-acting water-soluble benzodiazepine that provides anxiolysis and anterograde amnesia and can be given orally with few adverse effects. We evaluated the benefit and safety of oral midazolam for sedation of young children during voiding cystourethrography or nuclear cystography. SUBJECTS AND METHODS: For 3.5 years, a highly selected group of 98 children, ages 23 months to 9 years (mean, 4 years), were given oral midazolam 0.6 mg/kg 20-30 min before cystourethrography or nuclear cystography. These children either had been frightened by a previous catheterization (39%) or seemed particularly frightened during an examination of their genitals in the office (61%). A control group of 25 children, similar in age to the study group, did not receive midazolam before cystourethrography. Parents were interviewed to assess their child's recollection of the procedure. Voiding dynamics were assessed by evaluating the postvoiding radiograph. RESULTS: Of the midazolam-treated patients, 60% had no recollection of the study, and 31% remembered part or all of the study but did not have a negative experience. No significant change in vital signs or oxygen saturation was observed in any child. In the control group, 24 (96%) of 25 children remembered the cystographic examination (p < .01). Behavioral side effects occurred in 12% of the children receiving midazolam and consisted primarily of combative behavior as the medication was wearing off. Ninety-five percent of the parents indicated that they would want their child to have midazolam again if the cystography needed to be repeated. Of the children receiving midazolam, 76% had little or no residual urine after voiding, compared with 72% of the control group (no significant difference). CONCLUSION: In children who have been or are likely to be excessively frightened during cystourethrography or nuclear cystography, midazolam usually provides satisfactory amnesia and anxiolysis with few side effects or adverse impact on voiding dynamics.

Administration, Oral↗
PubMed1999

Midazolam metabolism by modified Caco-2 monolayers: effects of extracellular protein binding.

It has been suggested that the binding of a drug to plasma proteins will influence the intestinal extraction efficiency when drug is delivered to the mucosal epithelium via either the gut lumen or vasculature. We evaluated this hypothesis using cytochrome P-450 (CYP)3A4-expressing Caco-2 monolayers as a model for the intestinal epithelial barrier and midazolam as a CYP3A-specific enzyme probe. The rate of 1'-hydroxylation was measured following apical or basolateral midazolam administration to monolayers incubated in the presence or absence of 4 g/dl of human serum albumin (HSA) in the basolateral compartment medium. The midazolam-free fraction in culture medium containing HSA was 3.3%. Inclusion of HSA in the basolateral medium decreased peak intracellular midazolam accumulation after an apical midazolam dose (3 microM) by 35% and reduced the 1'-hydroxymidazolam formation rate by approximately 20%. Because of the accelerated diffusion of midazolam through the cell monolayer and into the basolateral compartment, there was a 61% reduction in the first-pass metabolic extraction ratio: 13.3 +/- 0. 12% for control versus 5.2 +/- 1% with HSA. Compared with control, addition of HSA resulted in a 91% decrease in the peak intracellular midazolam level and a 86% decrease in the rate of 1'-hydroxylation after the administration of midazolam into basolateral medium. These findings suggest that, in vivo, binding of a drug to plasma proteins will impact both first-pass and systemic intestinal midazolam extraction efficiency. Furthermore, the effect will be more pronounced for a drug that is delivered to mucosal enterocytes by way of arterial blood, compared with oral drug delivery.

Algorithms↗
PubMed1999

The effect of midazolam premedication on mental and psychomotor recovery in geriatric patients undergoing brief surgical procedures.

UNLABELLED: To assess the effect of IV midazolam premedication on recovery of cognitive function, 90 geriatric patients (aged 65-81 yr) undergoing brief transurethral procedures were enrolled into this prospective, placebo-controlled, double-blinded study. In all cases, a standard general anesthetic was administered. Thirty minutes before operating room transfer, patients in Group 0.5 mg, Group 2 mg, and Group S received 0.5 mg of midazolam, 2 mg of midazolam, or an equal volume of saline, respectively. Before study-drug administration (baseline), at 15 min thereafter, as well as on arrival in the postanesthesia care unit (PACU), and at 60 min and 120 min, postoperatively, we administered a digit-symbol substitution test, a mini-mental test, a shape-sorter test, and a patient-generated 100-mm visual analog score (0 = minimal and 100 = maximal) for anxiety, sleepiness, and coordination. A 4-point scale was used to assess the degree of patient sedation at 7, 15, and 30 min after study-drug administration. Using a modified Aldrete scoring system, PACU discharge was determined by the PACU staff. Patient anxiety, sleepiness, and coordination scores at baseline and at 15 min after study-drug administration were similar. When compared with saline, midazolam was associated with a significantly (P < 0.05) higher incidence of "deep" sedation. In Group 2 mg, the incidence of a low preoperative Spo2 (<94%) was significantly (P < 0.05) higher when compared with Group S. Emergence, extubation, and orientation times, as well as time to follow commands were unaffected by midazolam premedication. Postoperatively, the digit-symbol substitution test, mini-mental test, and shape-sorter test were similar among the groups. However, time to PACU discharge was significantly (P = 0.03) longer in the two midazolam treatment groups (41 +/-25 min, 60 +/- 32 min, 53 +/- 39 min for Groups S, 0.5 mg, and 2 mg, respectively). Finally, patient satisfaction was unaffected by the randomization schedule. IMPLICATIONS: IV premedicant midazolam 0.5 mg or 2 mg does not adversely affect mental and psychomotor recovery in geriatric patients undergoing brief surgical procedures. However, midazolam administration significantly prolonged postanesthesia care unit discharge time. Finally, during the preoperative period, midazolam increases the incidence of a Spo2 <94% in a dose-dependent manner.

Aged↗
PubMed2000

Pediatric pharmacodynamics of midazolam oral syrup. Pediatric Pharmacology Research Unit Network.

In this study, the authors evaluate the pharmacodynamics, safety, and acceptability of a new cherry-flavored oral syrup formulation of midazolam. This randomized, double-blind, parallel-group, dose-ranging clinical trial of oral midazolam was conducted at seven U.S. health care institutions focused on pediatric clinical pharmacology research (i.e., the PPRU Network). Pediatric patients (n = 85, ages 6 months through 15 years) underwent invasive procedures and were randomized to a single oral dose of midazolam syrup (0.25, 0.5, or 1.0 mg/kg). Patient taste acceptability of midazolam syrup was evaluated at the time of oral administration. Pharmacodynamic measurements included (1) sedation score using a 5-point scale at baseline and 10-, 20-, and 30-minute postdose intervals and (2) anxiety score using a 4-point scale at the time of separation from caretakers and, when applicable, at the time of mask anesthetic induction. Midazolam and alpha-hydroxymidazolam plasma concentrations were measured at all pharmacodynamic measurement time points. Adverse events were monitored continuously during the study. Most patients (99%) accepted the syrup without difficulty. Satisfactory sedation was achieved within 30 minutes by 81% of patients. The anxiety score at the time of caretaker separation and mask anesthetic induction was satisfactory for 87% and 91% of patients, respectively. A significant linear relationship between plasma drug concentration and maximal sedation score, but not anxiety score, was observed. The occurrence of adverse events was consistent with the known safety profile of midazolam. The most commonly reported adverse events were hiccoughing, hypoxemia, nausea, and emesis. It was concluded that a new oral syrup formulation of midazolam, 0.25 to 1.0 mg/kg, effectively induced rapid-onset, dose-related, adequate, and safe sedation and anxiolysis in pediatric patients who underwent operative procedures. Sedative effects were related to plasma concentrations of both midazolam and the primary metabolite, alpha-hydroxymidazolam. Oral midazolam, 1.0 mg/kg, administered within 30 minutes of the expected procedure or anesthetic induction should provide safe and effective sedation to a majority of children ages 6 months to 16 years.

Administration, Oral↗
PubMed2001

Midazolam sedation in mechanically ventilated newborns: a double blind randomized placebo controlled trial.

OBJECTIVE: To determine efficacy of midazolam as a sedative in mechanically ventilated newborns. DESIGN: Double blind randomized placebo controlled trial. SETTING: Neonatal Unit of Tertiary Hospital. OUTCOME: Sedation over 48 h of observation. METHODS: Neonates with birth weight less than 2000 g who were mechanically ventilated within 7 days of life were randomly assigned to midazolam and placebo group. Midazolam and placebo were administered as bolus (0.2 mg/kg) followed by continuous infusion (0.06 mg/kg/h). Both groups received morphine infusion (10 microg/kg/h). Sedation score was noted at 6 hourly intervals for 48 hours. Hemodynamic variables, ventilatory variables, complications and side effects of treatments were also recorded. RESULTS: Thirty-three neonates were enrolled (17 in midazolam, 16 in placebo group). The groups were comparable for birth weights and gestation. The midazolam group had significantly better sedation from 18-24 hours after enrollment compared to placebo group. At 48 h there were no significant differences in proportion of infants with adequate sedation between midazolam and placebo group. The two groups were comparable with respect to heart rate, perfusion, ventilatory indices and blood gas parameters. None of the infants were noted to have hypotension on loading with midazolam or placebo. Seizures were noted in 2 neonates in placebo group 24 hours after enrollment (insignificant statistically). CONCLUSION: Sedation provided by continuous infusion of midazolam and morphine appears to be comparable to morphine alone in newborn babies on mechanical ventilation, with no significant adverse effects. The course of mechanical ventilation is not influenced by use of midazolam.

Procedural Sedation↗
PubMed2002

Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokinetic-pharmacodynamic analysis.

BACKGROUND: Oral midazolam is widely used for preoperative sedation in children. We have studied the pharmacokinetics (PK) of both midazolam and its active 1-hydroxy metabolite and their contributions to sedative effect in 45 children attending for day surgery. METHODS: Blood samples (two per individual) were collected at the beginning and end of the surgical procedure. Plasma midazolam and 1-hydroxymidazolam (1-OHMDZ) were measured by HPLC. Sedation score (score: 1 = awake, 2 = drowsy/asleep) was recorded at the same time as the first blood sample. The population-PK software P-Pharm was used to analyse the data. Age, weight, sex, concomitant drugs, and the metabolic ratio, 1-OHMDZ/midazolam were investigated as co-variates of the PK of midazolam and 1-OHMDZ. The pharmacokinetic-pharmacodynamic (PK-PD) modelling of the score in relation to plasma midazolam and 1-OHMDZ was performed using logistic regression analysis. RESULTS: A median dose of 0.5 mg kg-1 was given to the children, median age 5 yr (range from 9 months to 12 yr) and weight 21 kg (range 8-75 kg). Average concentrations of midazolam 150 ng ml-1 and 1-OHMDZ 90 ng ml-1 were observed in the first plasma samples. These concentrations resulted in an odds ratio of 4 in favour of score 2 vs 1. The best PK-PD model included both midazolam and 1-OHMDZ as active moieties and predicted correct scores in 86% of cases. CONCLUSION: Studies of midazolam should evaluate the contribution of 1-OHMDZ to the overall PD effect. The metabolite 1-OHMDZ has approximately half the activity of the parent drug and can compensate for at least part of the decreased effect due to increased midazolam metabolism.

Administration, Oral↗
PubMed1991

[Epidural midazolam for treatment of postoperative pain].

Postoperative pain relief and sedation with epidural midazolam were studied. Twenty-one patients for elective upper abdominal surgery were divided into 3 groups. Epidural catheter was inserted into thoracic epidural space before induction of general anesthesia. In each group, either 10 ml saline only, midazolam 0.05 mg.kg-1 + 10 ml saline, or midazolam 0.1 mg.kg-1 + 10 ml saline was injected into epidural catheter for complaint of pain in recovery room. For 120 minutes after epidural injection, blood pressure, heart rate, respiratory rate, serum concentration of midazolam, and sedation score were monitored. In midazolam injected groups, only slight changes were seen in blood pressure, heart rate, and respiratory rate. Sedation score was graded from 1 to 6:1 means complete sleep, and not responded to verbal command, 6 means agitated and many complaints. Midazolam 0.1 mg.kg-1 + 10 ml saline group had the lowest score, and saline 10 ml group had the highest score. Prolonged sedation and pain relief were obtained in midazolam injected group, especially 0.1 mg.kg-1 + 10 ml saline group. Serum midazolam concentrations were lower than 200 ng.ml-1. These values were considered as the lower limit for sedation by intravenous administration. In conclusion, epidural midazolam was useful for postoperative pain relief. The mechanism is considered to involve spinally mediated CNS action or direct spinal action.

Adult↗
PubMed1990

Pharmacology of Dormicum (midazolam) and Anexate (flumazenil).

Midazolam and flumazenil have some characteristics in common which make them suitable partners as benzodiazepine (BZD) agonist and antagonist. After intravenous (i.v.) administration, both drugs are rapidly distributed into similar distribution volumes, from which they are cleared with a comparable short elimination half-life (t1/2 beta) in the range of 1 h (flumazenil) to 3 h (midazolam). Both drugs undergo hepatic metabolisation with a relatively high hepatic extraction ratio of around 0.3 for midazolam and 0.6 for flumazenil. The metabolisation of midazolam and flumazenil may equally be affected by considerable loss of active liver cells or by temporarily reduced hepatic blood flow. In such a case, elimination of both drugs may be prolonged in the same way. Flumazenil has only an inactive metabolite. The main active alpha-hydroxy-metabolite of midazolam does not contribute much to the activity of midazolam after parenteral administration. Its potency is lower than that of midazolam and its shorter elimination half-life (0.8 h) does not prolong the activity of the parent drug. As indicated by the therapeutic index, both drugs have a very high safety margin, which is considerably higher than that of thiopentone or propofol. Only low doses of both drugs are necessary to produce initial effects. Increasing doses intensify the drug activity and a ceiling effect is observed after maximal doses of midazolam and flumazenil. The onset of effect immediately follows the diffusion of the substances into the CNS and can be observed within the first minutes following flumazenil or midazolam administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Effects of diazepam and midazolam on baroreflex control of heart rate and on sympathetic activity in humans.

The effects of induction of anesthesia with diazepam and midazolam on baroreflex control of heart rate and on plasma levels of catecholamines were investigated in this study. Group 1 subjects (n = 10) received diazepam, 0.4 mg/kg. Group 2 subjects (n = 10) received midazolam, 0.3 mg/kg. Baroreflex function was assessed using a pressor test (phenylephrine). In addition, samples for subsequent determination of plasma norepinephrine and epinephrine levels and plasma diazepam or midazolam concentrations were collected before and 5, 10, and 15 min after intravenous drug administration. The pressor baroreflex slope declined significantly after diazepam or midazolam administration with the maximal changes (-45 and -43%, respectively) observed when plasma diazepam or midazolam concentrations were the highest. Norepinephrine plasma concentrations decreased at each measurement with both drugs. In contrast, epinephrine concentration decreased only after midazolam. The authors conclude that diazepam or midazolam used for induction of anesthesia results in a transient depression of baroreflex function and a sustained decrease of sympathetic tone. This study also indicates that the depression of arterial baroreflex heart rate responses under diazepam or midazolam anesthesia are less pronounced than the depression of baroreflex responses reported by other investigators with potent inhalational anesthetics. However, this disruptive effect of diazepam and midazolam on sympathetic control of circulation might induce a limited ability to compensate for hemodynamic alterations related to hypovolemia.

Adult↗
PubMed1994

Metabolic and subjective responses to oral diazepam and midazolam.

Diazepam premedication decreases the overall metabolic rate and oxygen consumption. Whether its properties are shared by midazolam is not known. In this study, eight healthy male volunteers were given oral diazepam (10 mg), midazolam (15 mg) and placebo in a random double-blind cross-over fashion. Metabolic responses were measured using an indirect calorimetry device. Subjective responses were measured using a visual analogue scale. Plasma concentrations of diazepam, midazolam and desmethyldiazepam were analysed and correlated to changes in metabolic and subjective responses. When compared to placebo, both diazepam and midazolam significantly decreased oxygen consumption (P < 0.01 in pairwise comparisons) and energy expenditure (P < 0.01 in pairwise comparisons). While there was a significant correlation between the plasma concentrations of diazepam and the changes in metabolic parameters, no such correlation was found with midazolam. Both diazepam and midazolam were subjectively more sedative than placebo (P < 0.05). There was no significant difference between the sedative effects of diazepam and midazolam, but diazepam was subjectively better tolerated than midazolam. These results indicate that both diazepam and midazolam, in addition to their CNS effects, significantly decrease the overall metabolic rate and oxygen consumption in healthy volunteers.

Administration, Oral↗
PubMed1993

[Acceptance, side-effects and reactive ability after medicamentous anxiolysis with midazolam. A prospective study with 519 gastroscopy and 506 colonoscopy patients].

In a prospective study 519 patients had gastroscopy (393 with and 126 without midazolam-premedication) and 506 patients had colonoscopy (377 with and 129 without midazolam-premedication) to evaluate acceptance, adverse reactions and reactivity after midazolam-premedication in outpatients immediately and 24 hours later by standard telephone interview. Patients could choose whether they would have midazolam or not. Normally 2 mg midazolam for gastroscopy and 4 mg for colonoscopy were given intravenously directly before endoscopy. 71.5% of gastroscopy and 75.3% of colonoscopy patients who received midazolam afterwards accepted endoscopy only with premedication. 27.7% of our gastroscopy and 14.1% of the colonoscopy patients who than received midazolam were beforehand unable to decide about premedication by themselves. 27.5% of the gastroscopy and 13.8% of the colonoscopy group were persuaded to have midazolam by the doctor examining. 12.7% of our gastroscopy- and 27.1% of our colonoscopy-patients who wished to have midazolam were persuaded to withdraw from it. There were no cardio-pulmonal complications but fatigue was found in 35.4% of the gastroscopy Patients with and 11.9% of those without premedication; colonoscopy patients: 50.4% with and 34.9% without premedication. The incidence of headache was: gastroscopy patients: 6.4% vs. 4%; colonoscopy patients: 11.1% vs. 10.9%. Dizziness: gastroscopy patients: 6.4% vs. 3.2%; colonoscopy patients: 7.6% vs. 7%. Nausea and vomiting were rare (0 to 5%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

[Pharmacokinetics of midazolam in patients with liver damage for hepatectomy].

Pharmacokinetics of midazolam in patients with liver damage for hepatectomy was compared to that in patients without liver injury for gastrectomy. Anesthesia was induced with midazolam 0.15 mg.kg-1 and fentanyl. Serum concentration of midazolam was measured at 30 minutes, 1, 2, 3, 4, 6 and 8 hours after midazolam injection. Serum midazolam levels were not significantly different between the two groups at any time. The elimination half-life of midazolam was about 3 times longer in hepatectomy group (24.2 hours) than in the group without liver injury (8.4 hours). Area under the curve of the serum midazolam concentration was larger in the group with liver damage than in the group without it. But distribution volume and clearance of midazolam were not different between the two groups probably because of more blood transfusion and bleeding in hepatectomy group. The recovery time from anesthesia in hepatectomy group was as long as that in the group without liver injury. The results suggest that in patients with liver damage for hepatectomy, the elimination of midazolam is prolonged but its effect is not.

Aged↗