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PubMedDate not supplied

Urinary screening for midazolam and its major metabolites with the Abbott ADx and TDx analyzers and the EMIT d.a.u. benzodiazepine assay with confirmation by GC/MS.

Midazolam is a short-acting 1,4-imidazole benzodiazepine with sedative-hypnotic, anxiolytic, and amnestic properties. It is administered orally for sleeping disorders and intravenously for sedation during surgery. This drug has a short half-life (1.5-3.5 h), with less than 1% of a midazolam dose being excreted unchanged. The major urinary metabolite is alpha-hydroxy midazolam glucuronide. The objective of this study was to characterize the reactivity of midazolam and its two major metabolites in the EMIT d.a.u. benzodiazepine assay and in the Abbott TDx and ADx urine benzodiazepine assays. Midazolam and alpha-OH midazolam gave an equivalent response to the EMIT low calibrator at 200 ng/mL. On both Abbott analyzers, midazolam and alpha-OH midazolam gave an equivalent net polarization at 500 ng/mL to the Abbott low control. All three screening assays were positive in all of 21 random urine specimens collected from midazolam-treated patients. Confirmation testing was performed by analyzing for alpha-OH midazolam after enzymatic hydrolysis and formation of a TMS derivative for GC/MS. All urine specimens were confirmed positive for alpha-OH midazolam. In conclusion, all three immunoassay screening assays are acceptable for detecting the presence of midazolam metabolites in urine.

Autoanalysis↗
PubMed2000

Changes in cerebral venous prostanoids during midazolam-induced cerebrovascular hypotension in newborn piglets.

OBJECTIVES: We hypothesized that the effects of midazolam are associated with altered prostanoid synthesis in the newborn piglet during continuous infusion. To test this hypothesis, we examined the effect of midazolam on prostanoid production in the carotid artery and sagittal sinus vein before and during midazolam infusion. DESIGN: Prospective, randomized, controlled, experimental study. SETTING: Research laboratory at Long Beach Memorial Medical Center. SUBJECTS: Fourteen newborn piglets (1-3 days old, 1-1.5 kg) randomly assigned to receive either midazolam or vehicle (5% dextrose) infusion for 6 hrs. INTERVENTIONS: Two groups of animals received either a) a loading dose of 300 microg/kg of midazolam over 15 mins, followed by a continuous intravenous infusion of 100 microg/kg/hr (n = 6), or b) equivalent volume bolus and intravenous infusions of 5% dextrose (control, n = 8). MEASUREMENTS AND MAIN RESULTS: Changes in systemic and cerebral venous hemodynamics, blood gases, and prostanoid (prostaglandin E2, 6-ketoprostaglandin F1 alpha, thromboxane B2) production were measured at baseline, postbolus, and at 0.5, 2, 4, and 6 hrs. Systemic and cerebral venous midazolam concentrations were measured at 0.5, 1, 2, 3, 4, 5, and 6 hrs. Midazolam infusion did not affect systemic hemodynamics or blood gases. In contrast, midazolam infusion significantly reduced sagittal sinus vein blood pressure, PO2, oxygen saturation, and oxygen content. Cerebral fractional oxygen extraction increased and was positively correlated with cerebral fractional midazolam extraction. Concurrently, systemic and sagittal sinus vein plasma prostaglandin E2 concentrations decreased, whereas 6-ketoprostaglandin F1 alpha concentrations increased with midazolam infusion. Thromboxane B2 concentrations increased transiently in the systemic plasma. CONCLUSIONS: Midazolam infusion preceded by a high bolus dose in newborn piglets alters systemic and sagittal sinus vein prostanoid production. It is also associated with changes in sagittal sinus vein blood pressure and cerebral fractional oxygen extraction. These changes may reflect decreased brain perfusion and metabolism during midazolam infusion.

Analysis of Variance↗
PubMed2004

A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients.

OBJECTIVES: To determine if midazolam is superior to lorazepam or haloperidol in the management of violent and severely agitated patients in the emergency department. Superiority would be determined if midazolam resulted in a significantly shorter time to sedation and shorter time to arousal. METHODS: This was a randomized, prospective, double-blind study of a convenience sample of patients from an urban, county teaching emergency department. Participants included 111 violent and severely agitated patients. Patients were randomized to receive intramuscular midazolam (5 mg), lorazepam (2 mg), or haloperidol (5 mg). RESULTS: The mean (+/-SD) age was 40.7 (+/-13) years. The mean (+/-SD) time to sedation was 18.3 (+/-14) minutes for patients receiving midazolam, 28.3 (+/-25) minutes for haloperidol, and 32.2 (+/-20) minutes for lorazepam. Midazolam had a significantly shorter time to sedation than lorazepam and haloperidol (p < 0.05). The mean difference between midazolam and lorazepam was 13.0 minutes (95% confidence interval [95% CI] = 5.1 to 22.8 minutes) and that between midazolam and haloperidol was 9.9 minutes (95% CI = 0.5 to 19.3 minutes). Time to arousal was 81.9 minutes for patients receiving midazolam, 126.5 minutes for haloperidol, and 217.2 minutes for lorazepam. Time to arousal for midazolam was significantly shorter than for both haloperidol and lorazepam (p < 0.05). The mean difference in time to awakening between midazolam and lorazepam was 135.3 minutes (95% CI = 89 to 182 minutes) and that between midazolam and haloperidol was 44.6 minutes (95% CI = 9 to 80 minutes). There was no significant difference over time by repeated-measures analysis of variance between groups in regard to changes in systolic and diastolic blood pressure (p = 0.8965, p = 0.9581), heart rate (p = 0.5517), respiratory rate (p = 0.8191), and oxygen saturation (p = 0.8991). CONCLUSIONS: Midazolam has a significantly shorter time to onset of sedation and a more rapid time to arousal than lorazepam or haloperidol. The efficacies of all three drugs appear to be similar.

Adult↗
PubMed1991

[Epidural administration of midazolam with saline or bupivacaine for postoperative pain].

Postoperative pain relief and sedation with epidural midazolam-saline or midazolam-bupivacaine were studied in 46 patients after elective upper abdominal surgery. They were divided into 6 groups. In each group, 10 ml saline, 10 ml saline+midazolam 0.05 mg.kg-1, 10 ml saline+midazolam 0.1 mg.kg-1 (saline group), 0.25% bupivacaine 6 ml, 0.25% bupivacaine 6 ml + midazolam 0.05 mg.kg-1 or 0.25% bupivacaine 6 ml + midazolam 0.1 mg.kg-1 (bupivacaine group) was administered via epidural catheter for complaint of pain. For 120 minutes after epidural injection, blood pressure (BP), heart rate (HR), respiratory rate (RR), sedation score, and serum concentration of midazolam (conc midazolam) were evaluated. The time interval until next complaint of pain (pain relief time) was measured. In midazolam injected group, BP, HR, RR were not changed from preinjection value, but sufficient sedation was obtained and pain relief time was significantly prolonged compared with saline or bupivacaine injected group. Midazolam level was lower than that of sedation level. There were no significant differences between saline group and bupivacaine group, but the pain relief effect was slightly stronger in bupivacaine group. It is concluded that epidural saline - midazolam or 0.25% bupivacaine - midazolam is useful for postoperative pain relief after upper abdominal surgery.

Abdomen↗
PubMed1987

Use of midazolam hydrochloride in anesthesia.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, dosage, and cost and availability of midazolam hydrochloride are reviewed. The anxiolytic, sedative, hypnotic, anticonvulsant, muscle-relaxant, and amnesic properties of midazolam are similar to those of other injectable benzodiazepines. Midazolam is approximately two to four times as potent as diazepam. Midazolam hydrochloride is water soluble (resulting in fewer local adverse reactions after injection), has a rapid onset and short duration of action, and causes relatively mild cardiovascular and respiratory effects. The drug generally is well tolerated. Midazolam is a good premedicant for general or regional anesthesia. Its greatest use will probably be for conscious sedation during surgical or diagnostic procedures performed under local or regional anesthesia. Induction of anesthesia with midazolam alone is somewhat unpredictable; opiate pretreatment makes induction more consistent. Midazolam is a less reliable induction agent than thiopental, but because it produces fewer adverse cardiovascular and respiratory effects than thiopental, midazolam appears to be a safer induction agent for elderly patients or patients with cardiovascular disease. The recommended dose of midazolam for preoperative sedation is 0.07-0.1 mg/kg given by intramuscular injection one hour before surgery. For conscious sedation, 0.1-0.15 mg/kg intravenously in divided doses is usually adequate. Lower doses of midazolam are recommended for elderly or debilitated patients and patients who have severe liver disease. The costs of equipotent doses of midazolam and injectable diazepam are similar. An oral dosage form is under investigation in the United States. Midazolam's pharmacologic and pharmacokinetic profile makes it an attractive alternative to other injectable benzodiazepines used in anesthesia.

Amnesia↗
PubMed1995

Drug discrimination analysis of midazolam under a three-lever procedure: I. Dose-dependent differences in generalization and antagonism.

Twelve rats were trained to discriminate two doses of midazolam, 0.32 and 3.2 mg/kg, from no drug under a three-lever, multiple-trials procedure (15-min time-out, 5-min fixed-ratio-10 schedule of food reinforcement). In tests, midazolam (0.0032-10 mg/kg), administered cumulatively within a session or acutely across sessions, produced dose-dependent increases in responding on the low-dose lever after 0.1 to 1.0 mg/kg and on the high-dose lever at higher doses in all rats. Flumazenil dose-dependently antagonized the discriminative stimulus effect of 3.2 mg/kg of midazolam in all rats but antagonism of the lower midazolam training dose was not obtained in all rats. Pentobarbital dose-dependently produced responding on the levers associated with the no-drug and 0.32-mg/kg midazolam conditions but not on the lever associated with 3.2 mg/kg of midazolam. These results differed from those that would have been predicted from studies in midazolam-trained rats in two-lever procedures. The muscle relaxant methocarbamol and nonsedative/anxiolytic drugs (morphine, caffeine and d-amphetamine) did not produce responding on the lever associated with either the low or high midazolam training dose. However, cocaine produced partial responding on the lever associated with the low midazolam dose. Thus, the discriminative stimulus effects of 3.2 mg/kg of midazolam were benzodiazepine-like and not a function of general sedative or muscle-relaxant effects. The 0.32-mg/kg midazolam training dose, in this context, appeared less specific than 3.2 mg/kg of midazolam. Taken together, the results suggest that not all differences among the training stimuli in this three-lever context reflect simple differences in dose.

Animals↗
PubMed1998

Medetomidine-midazolam sedation in sheep.

Seven sheep were sedated 3 times: with medetomidine (15 micrograms kg-1), with midazolam (0.1 mg kg-1) and with a combination of the drugs. All drugs were administered intravenously. Heart and respiratory rates were measured. Arterial blood samples were collected, and PaO2, PaCO2, pH, haemoglobin concentration and saturation, and base excess were determined. Systolic and mean arterial pressures were recorded before and after the treatment with medetomidine-midazolam. Midazolam increased the time of recumbency induced by medetomidine. After administration of midazolam alone, 4 of the 7 sheep were sedated and the other 3 were excited. Heart rate decreased after both medetomidine and medetomidine-midazolam. One sheep suffered a cardiac arrest after medetomidine-midazolam injection, and it required resuscitation. PaO2 and haemoglobin oxygen saturation decreased after medetomidine, and medetomidine-midazolam caused a marked hypoxaemia. PaCO2 increased after medetomidine, both alone and combined with midazolam, but arterial pH was within the reference values after all drug administrations. Systolic and mean arterial pressures decreased after medetomidine-midazolam. This study indicates that though in sheep midazolam potentiates the sedative effect of medetomidine, the combination of medetomidine and midazolam also reduces the in PaO2 and haemoglobin oxygen saturation more than medetomidine alone. The results indicate that a medetomidine-midazolam combination is unsafe for sheep at the doses studied.

Animals↗
PubMed1999

Midazolams cardiac depressant effects and their lack of reversal by flumazenil in isolated rabbit hearts.

Midazolam is known to cause a dose-dependent increase and decrease in the contractile force of the myocardium. Whether flumazenil can reverse these effects of midazolam remains unclear. In this study, we determined the cardiac effects of midazolam and the counter effect of flumazenil on midazolam-induced myocardial depression in isolated rabbit hearts. Rabbit hearts were isolated and perfused using the Langendorff technique, and left ventricle pressure and heart rate were measured by a pressure transducer in the left ventricle. One set of hearts were perfused with increasing concentrations of midazolam for 10 min, another set were perfused with concomitant midazolam and flumazenil. Concentrations of 5, 10, 20 and 50 microM midazolam decreased left ventricle pressure significantly (P < 0.01, P < 0.05, P < 0.01, P < 0.01, respectively). Heart rates decreased with concentrations of 10, 20 and 50 microM midazolam (P < 0.01, P < 0.01, P < 0.05, respectively). Flumazenil had no effect on the midazolam-induced decrease in left ventricle pressure and heart rate. Midazolam decreased the cardiac contractile force and heart rate of isolated rabbit hearts in a concentration-dependent manner. The failure of flumazenil to reverse these effects suggest that this cardiac depressant effect of midazolam is not mediated through peripheral benzodiazepine receptors.

Anesthetics, Intravenous↗
PubMed1981

The pharmacokinetics of midazolam in man.

Midazolam, a new water-soluble benzodiazepine, was administered as: i) 5 mg intravenously, ii) a 10-mg oral solution and iii) a 10-mg oral tablet, to six volunteers whose informed consent had been obtained. Midazolam plasma concentrations were measured using an electron-capture gas-liquid chromatographic assay. After 5-mg intravenous midazolam, subjects fell asleep within 1-2 min and continued to sleep for an average of 1.33 h. After oral midazolam intake (solution or tablets), drowsiness appeared after a average of 0.38 h (range 0.25-0.55 h) and sleep continued for an average of 1.17 h. The time to reach peak plasma midazolam concentration after the 10-mg solution dose (0.37 +/- 0.45 h) did not differ significantly ('t' = 2.04, df = 10, p greater than 0.05) from the time to reach peak plasma midazolam level after the 10-mg tablet dose (0.74 +/- 0.45 h). The terminal half-life, (t 1/2), of midazolam in plasma was 1.77 +/- 0.83 h and there was no significant difference between the mean terminal half-life values obtained for the three midazolam formulations. The mean total clearance (Cl), of midazolam after 5-mg intravenous administration was 0.383 +/- 0.0941 . kg-1 . h-1. The first pass effect, F, determined experimentally (0.36 +/- 0.09) indicated the substantial first pass metabolism of midazolam. The percentage of the midazolam dose excreted unchanged in urine in four subjects during the 0-8-h urine collection interval was very small (0.011%-0.028%).

Adult↗
PubMed1996

[Anxiolysis, sedation, and stress reduction following oral premedication with midazolam in adults. A comparison with dipotassium clorazepate and placebo].

Benzodiazepines are the most commonly used anxiolytic agents. Among the benzodiazepines, midazolam has the advantage of a short elimination half-life, which is especially useful in outpatient surgery. However, in contrast to other commonly prescribed benzodiazepines, such as chlorazepate dipotassium, oral premedication with midazolam has not been thoroughly investigated. Therefore, the present study was performed to compare anxiolysis, sedation and stress reduction with midazolam and clorazepate dipotassium in adults. METHODS. After IRB approval and informed consent had been obtained, 85 patients scheduled for breast biopsy were studied. The patients were chosen at random to receive either 7.5 mg midazolam (n = 29), 20 mg clorazepate dipotassium (n = 28) or placebo (n = 28) preoperatively. Before premedication, immediately prior to surgery and postoperatively in the recovery room, the following parameters were determined with visual analogue scales (VAS): "asthenia," "depression," oral salivation, muscle tension, motoric restlessness and sweating of the palms. In addition, anxiety (STAI-G-X-1, Spielberger), heart rate and arterial blood pressure were measured. Before patients underwent surgery, the degree of sedation was evaluated by the anaesthesiologist. RESULTS. Clorazepate dipotassium and midazolam both caused a reduction in anxiety as compared with the placebo (P < 0.05). Only clorazepate dipotassium reduced anxiety postoperatively (P < 0.05). Neither midazolam nor clorazepate dipotassium caused a reduction in "asthenia" and "depression." Midazolam was more effective in preventing increased blood pressure than clorazepate dipotassium and the placebo (P < 0.05). Furthermore, after premedication with midazolam, salivation, muscle tension, motoric restlessness and sweating of the palms remained stable, in contrast to the results after premedication using clorazepate dipotassium or placebo (P < 0.05). CONCLUSIONS. The anxiolytic effects of 7.5 mg midazolam and 20 mg clorazepate dipotassium were similar after oral application. However, the anxiolytic effect of midazolam is shorter-lived than that of clorazepate dipotassium. In contrast to clorazepate dipotassium, midazolam produced no increase in arterial blood pressure and stabilized oral salivation, production in the palms, muscle tension and motoric restlessness.

Adult↗
PubMed2004

Combined discriminative stimulus effects of midazolam with other positive GABAA modulators and GABAA receptor agonists in rhesus monkeys.

RATIONALE: Interactions among compounds at GABA(A) receptors might have important implications for the therapeutic and other effects of positive GABA(A) modulators (e.g. benzodiazepines). OBJECTIVES: This study examined whether a midazolam discriminative stimulus is modified by GABA(A) agonists that act at sites other than benzodiazepine sites. METHODS: Rhesus monkeys discriminating midazolam (0.32 mg/kg SC) received direct-acting GABA(A) receptor agonists (e.g. muscimol and gaboxadol), an indirect-acting GABA(A) receptor agonist (progabide), ethanol, another benzodiazepine (triazolam), a barbiturate (pentobarbital), or a neuroactive steroid (pregnanolone) alone and in combination with midazolam. RESULTS: When administered alone, triazolam (0.1 mg/kg), pentobarbital (17.8 mg/kg) and pregnanolone (5.6 mg/kg) occasioned high levels of midazolam lever responding, ethanol (1-3 g/kg) occasioned intermediate levels of midazolam lever responding, and muscimol (0.32-1 mg/kg), gaboxadol (3.2-10 mg/kg) and progabide (10-32 mg/kg) occasioned low levels of midazolam lever responding. When combined with less-than-fully effective doses of midazolam, progabide (32 mg/kg) and ethanol (1 g/kg), but not muscimol and gaboxadol, enhanced the midazolam discriminative stimulus. Triazolam, pregnanolone and pentobarbital increased the potency of midazolam to occasion midazolam lever responding and the effects of these combinations were additive. CONCLUSIONS: Direct-acting GABA(A) receptor agonists are qualitatively different from positive GABA(A) modulators in rhesus monkeys trained to discriminate midazolam. Although GABA(A) receptor agonists and modulators can enhance the actions of benzodiazepines at the GABA(A) receptor complex, the same drugs do not necessarily modify the discriminative stimulus effects of benzodiazepines. These results underscore the importance of the mechanism by which drugs alter Cl(-) flux at the GABA(A) receptor complex as a determinant not only of drug action but also of drug interaction and whether any particular drug enhances the behavioral effects of a benzodiazepine.

Animals↗
PubMed2003

Biphasic action of midazolam on GABAA receptor-mediated responses in rat sacral dorsal commissural neurons.

The effect of the benzodiazepine agonist midazolam on gamma-aminobutyric acid(A) (GABA(A)) receptor-mediated currents was investigated in neurons acutely dissociated from the rat sacral dorsal commissural nucleus (SDCN) using the nystatin-perforated patch-recording configuration under voltage-clamp conditions. Midazolam displayed a biphasic effect on GABA responses. Low concentrations of midazolam (1nM-10 microM) reversibly potentiated GABA (3 microM)-activated Cl(-) currents (I(GABA)) in a bell-shaped manner, with the maximal facilitary effect at 0.1 microM; whereas at higher concentrations (above 10 microM), midazolam had an antagonistic effect on I(GABA). Our further study indicated that midazolam changed GABA(A) receptor affinity to GABA and the effects of midazolam on I(GABA) were voltage-independent. The benzodiazepine receptor antagonist, flumazenil, abolished the facilitary effect of low concentrations of midazolam rather than the antagonism of I(GABA) induced by high doses of midazolam. In addition, activation of protein kinase C prevented the inhibitory effect of midazolam at higher concentrations, but did not influence the effect of midazolam at low concentrations. These results indicate that midazolam interacts with another distinct site other than the central benzodiazepine receptors on GABA(A) receptors as an antagonist at higher concentrations in SDCN neurons.

Animals↗
PubMed2006

Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam.

OBJECTIVE: Our objective was to assess the effect of the antimycotic voriconazole on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. METHODS: We used a randomized, crossover study design. Ten healthy male volunteers were given either no pretreatment (control phase) or voriconazole (voriconazole phase) orally, 400 mg twice daily on the first day and 200 mg twice daily on the second day. Midazolam was given, either 0.05 mg/kg intravenously or 7.5 mg orally, 1 hour after the last dose of voriconazole and during the control phase. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and voriconazole were determined for 24 hours and pharmacodynamic variables measured for 12 hours. RESULTS: Voriconazole reduced the clearance of intravenous midazolam by 72% (P < .001) and increased its elimination half-life from 2.8 to 8.3 hours (P < .001). Voriconazole increased the peak concentration and the area under the plasma concentration-time curve of oral midazolam by 3.8- and 10.3-fold, respectively (P < .001). The bioavailability of oral midazolam was increased from 31% to 84% (P < .001). Voriconazole profoundly increased the psychomotor effects of oral midazolam (P < .001) but only weakly increased the effects of intravenous midazolam. CONCLUSION: When midazolam is given as small intravenous bolus doses, its effect is not increased to a clinically significant degree by voriconazole. The use of large midazolam doses increases the risk of clinically significant interactions also after its intravenous administration. The use of oral midazolam with voriconazole should be avoided, or substantially lower doses should be used.

Administration, Oral↗
PubMed2006

Midazolam amnesia and short-term/working memory processes.

We examined whether midazolam impairs short-term/working memory processes. We hypothesize that prior dissociations in midazolam's effects on short-term/working memory tasks and episodic memory tasks arise because midazolam has a larger effect on episodic memory processes than on short-term/working memory processes. To examine these issues, .03 mg/kg of participant's bodyweight of midazolam was administered in a double-blind placebo-controlled within-participant design. Performance on the digit span and category generation/recall tasks was examined. The results of Experiment 1 demonstrated that: (1) midazolam impaired performance on the digit span task; (2) midazolam did not impair performance on the category generation task; (3) midazolam impaired performance on the category recall task; and (4) midazolam's effect on category recall was four times as large as its effect on digit span. The results of Experiment 2 demonstrated that midazolam did not impair digit span performance when the digit span task was administered at a later time. These results suggest that midazolam can impair short-term/working memory processes, but these effects are substantially smaller than midazolam's effect on episodic memory processes. Moreover, they demonstrate that conscious awareness of materials during study is not sufficient to produce episodic memory.

Adult↗
PubMed1998

The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin.

OBJECTIVE: To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrates midazolam and clarithromycin. METHODS: On day 1, 16 volunteers (eight men and eight women; age range, 20 to 40 years; weight range, 45 to 100 kg) received simultaneous doses of midazolam intravenously (0.05 mg/kg over 30 minutes) and orally (4 mg of a stable isotope, 15N3-midazolam). Starting on day 2, 500 mg clarithromycin was administered orally twice daily for 7 days. On day 8, intravenous and oral doses of midazolam were administered 2 hours after the final clarithromycin dose. Blood and urine samples were assayed for midazolam, 15N3-midazolam, and metabolites by gas chromatography-mass spectrometry. RESULTS: There was no significant (p > 0.05) difference in the urinary excretion of 1'-hydroxymidazolam after intravenous and oral dosing on day 1 or day 8, indicating that the oral dose was completely absorbed into the gut wall. The oral clearance of midazolam was found to be significantly greater in female subjects (1.9 +/- 1.0 versus 1.0 +/- 0.3 L/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.35 +/- 0.1 versus 0.44 +/- 0.1 L/hr/kg). For women not receiving oral contraceptives (n = 6) a significant gender-related difference was observed for systemic and oral clearance and for area under the curve and elimination half-life after oral administration. A significant (p < 0.05) reduction in the systemic clearance of midazolam from 28 +/- 9 L/hr to 10 +/- 3 L/hr occurred after clarithromycin administration. Oral midazolam availability was significantly increased from 0.31 +/- 0.1 to 0.75 +/- 0.2 after clarithromycin dosing. Likewise, intestinal and oral availability were significantly increased from 0.42 +/- 0.2 to 0.83 +/- 0.2 and from 0.74 +/- 0.1 to 0.90 +/- 0.04, respectively. A significant correlation was observed between intestinal and oral availability (n = 32, r = 0.98, p < 0.05). After clarithromycin administration, a significant correlation was observed between the initial hepatic or intestinal availability and the relative increase in hepatic or intestinal availability, respectively. Female subjects exhibited a greater extent of interaction after oral and intravenous dosing than male subjects (p < 0.05). CONCLUSION: These data indicate that in addition to the liver, the intestine is a major site of the interaction between oral midazolam and clarithromycin. Interindividual variability in first-pass extraction of high-affinity CYP3A substrates such as midazolam is primarily a function of intestinal enzyme activity.

Adult↗
PubMed1991

Pharmacokinetic and pharmacodynamic study of midazolam in children during esophagogastroduodenoscopy.

We undertook a prospective study to evaluate the relationship between the onset and degree of sedation and the midazolam plasma concentration in children between 6 and 18 years of age during esophagogastroduodenoscopy. Thirteen boys and seven girls (median age 13.5 years) were studied. Midazolam was injected intravenously for 5 minutes, and the dose was titrated to sedation or a maximum dose of 0.1 mg/kg was given. Plasma midazolam concentration was determined just before and at 5, 10, 15, 30, 45, and 60 minutes after the start of midazolam injection. The patient's level of sedation was evaluated by an assistant at each blood sampling time. Clearance, volume of distribution, and terminal elimination (beta) half-life were estimated from a biexponential fit of the serial plasma midazolam concentrations. Mean beta half-life of midazolam was 47 +/- 26 minutes and mean clearance was 10.0 +/- 5.0 ml/min per kilogram of body weight. Maximum level of sedation occurred at 5 minutes after initiation of the injection and corresponded to a mean peak midazolam serum concentration of 229 +/- 39 micrograms/L. Thereafter, a decline of mean sedation scores paralleled the decrease in midazolam concentration. Mean oxygen saturation remained greater than 94% during the study. We conclude that children metabolize and excrete midazolam more rapidly than adults do and that sedation adequate for endoscopy is safely achieved in the majority of children with a midazolam dose of 0.05 to 0.1 mg/kg and a mean peak midazolam concentration greater than 200 microgram/L.

Adolescent↗
PubMed1992

Comparison of intravenous and endotracheal administration of midazolam and the effect on pulmonary function and histology in the lamb model.

OBJECTIVES: To determine the effect of endotracheal administration of midazolam on pulmonary function and histology in lambs. DESIGN: Prospective, randomized, controlled study. SETTING: Laboratory of the UpJohn Pharmaceutical Company. TYPES OF PARTICIPANTS: Twenty male and female lambs weighing 10 to 20 kg. INTERVENTIONS: The animals were anesthetized and placed on controlled ventilation. The animals were divided into four groups. The first two groups received endotracheal midazolam 0.1 and 0.2 mg/kg. The other two groups received IV midazolam 0.1 and 0.2 mg/kg. The endotracheal group had a catheter placed through the endotracheal tube, and midazolam was rapidly injected through the catheter followed by a 2-mL normal saline flush. Two rapid insufflations were administered, and the animals were then returned to the ventilator. Serum midazolam levels were drawn at one, two, five, ten, 15, and 20 minutes after both IV and endotracheal administration. Heart rate, respirations, SaO2 by oximetry, peak and mean airway pressure, compliance, airway resistance, and end-tidal CO2 were measured throughout the experiment. Lung sections were taken from control and treated animals receiving 0.1 and 0.2 mg/kg endotracheal midazolam, respectively. Sample lung sections were taken at 24, 48, and 120 hours after endotracheal midazolam administration. MEASUREMENTS AND MAIN RESULTS: There were no statistical or clinically significant differences for pulmonary function between endotracheally and IV-administered midazolam. Histologic examination of the lungs at 24, 48, and 120 hours after endotracheal midazolam showed no pathologic changes in the control and study animals. Acceptable serum midazolam levels were achieved endotracheally with no clinically deleterious effects. CONCLUSION: Endotracheal midazolam showed no significant deleterious effect on pulmonary function or histology in the lamb model.

Airway Resistance↗
PubMed1999

Continuous intravenous midazolam infusion for Centruroides exilicauda scorpion envenomation.

STUDY OBJECTIVE: We sought to describe the effects of continuous intravenous midazolam infusion as therapy for severe bark scorpion (Centruroides exilicauda) envenomation. METHODS: A retrospective chart review from July 1, 1993, through January 1, 1998, identified all patients treated at a university hospital with International Classification of Diseases, Ninth Revision, codes 989.5 (toxic effect of venom) or E905.2 (scorpion sting causing poisoning). By using standardized collection forms, data were extracted from the medical record of every patient who had a grade III or IV envenomation and was treated with a continuous intravenous midazolam infusion. RESULTS: Our search identified 104 patients; 34 had grade III or IV envenomation. Of these, 33 were treated in the ICU with continuous intravenous midazolam infusion. Median patient age was 4 years (range, 1 to 68 years). Midazolam dosage was adjusted to induce a light sleep state to control agitation and involuntary motor activity. The median amount of midazolam resulting in the first recorded decrease in agitation and involuntary motor activity was 0.30 mg/kg (range, 0.03 to 1.76 mg/kg). This first evidence of clinical improvement was recorded as 1.00 hour (median), with a range of 0.00 to 3.75 hours. The initial midazolam infusion rate was 0.10 mg x kg(-1) x h(-1) (median), with a range of 0.01 to 0.31 mg x kg(-1) x h(-1). The maximal midazolam infusion rate was 0.30 mg x kg(-1) x h(-1) (median), with a range of 0.06 to 1.29 mg x kg(-1) x h(-1). The median time until the maximal midazolam infusion rate was 2.5 hours (range, 0.00 to 8.50 hours). The median duration of infusion was 9. 50 hours (range, 4.25 to 20.50 hours). The median length of stay in the ICU was 15.17 hours (range, 6.0 to 28.0 hours), and 85% of patients were discharged directly home. All patients had resolution of abnormal motor activity and agitation during their midazolam infusion. Transient hypoxemia without evidence of end-organ dysfunction was documented in 4 patients during midazolam therapy. CONCLUSION: A continuous intravenous midazolam infusion can be a safe, effective, and readily available treatment option for patients with grade III or IV C exilicauda envenomation.

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