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PubMed2003

Correlation of the dose of midazolam for symptom control with administration periods: the possibility of tolerance.

Although tolerance to midazolam is sometimes described in the palliative care literature, no studies have systemically examined the possibility. To explore the association between midazolam dose for symptom palliation and the administration period, a retrospective study was performed on 62 terminally ill cancer patients who required parenteral midazolam in the final three days of life. The mean maximum dose and administration period of midazolam were 38 +/- 45 mg/day (median = 24) and 10 +/- 19 days (median = 2.5), respectively. Thirteen patients (21%) received midazolam at a dose of 60 mg/day or more, and 13 patients (21%) received it for 14 days or longer. The maximum doses were significantly correlated with patient age (rho = -0.32, P = 0.012) and the administration period (rho = 0.47, P < 0.01); and were significantly higher in patients who received midazolam for 14 days or longer (74 +/- 63 mg/day vs. 28 +/- 34 mg/day, P < 0.01). Multivariate analyses revealed that younger age (< or =70) and longer administration periods (> or =14 days) were independent determinants for a midazolam requirement of 60 mg/day or more (odds ratios [95% C.I.] = 0.091 [0.009 - 0.92], P = 0.042; 11 [2.3 - 54], P < 0.01; respectively). The significant correlation of midazolam doses with administration period suggests that the longer use of midazolam can result in the development of tolerance. This finding suggests that midazolam should be reserved for patients with limited prognoses.

Adjuvants, Anesthesia↗
PubMed2003

Phenotyping CYP3A using midazolam in cancer and noncancer Asian patients.

AIMS: To investigate CYP3A activity in cancer and noncancer Asian patients using midazolam and to reveal possible alternative traits for phenotyping CYP3A. METHODS: Intravenous midazolam 2.5 mg or 2.5-8 mg was administered to 27 cancer and 24 noncancer patients, respectively. Plasma was sampled at 0, 0.25, 0.5, 1, 1.5, 2, 3.5 and 5 h after intravenous ultrashort, 30 s infusion. Plasma midazolam and 1'-hydroxymidazolam concentrations were determined using GCMS. The disposition of midazolam and 1'-hydroxymidazolam in these patients was compared. Midazolam clearance was correlated with dose-normalized plasma midazolam concentrations (concentration/per dose). RESULTS: Clearance (CL) and steady state volume of distribution (Vss) of midazolam (mean +/- SD, 95% confidence level) in cancer (424 +/- 155, 61.3 ml min(-1); 1.21 +/- 0.46, 0.18 l kg(-1)) and noncancer (407 +/- 135, 57.1 ml min(-1); 1.15 +/- 0.33, 0.155 l kg(-1)) patients, respectively, were not different and comparable with published data. Clearance variability was 4-5 fold in both groups. Midazolam clearance correlated significantly with all plasma concentration/per dose at and after the 1-h time point, with a minimum correlation coefficient of r = 0.752, P < 0.001. CONCLUSIONS: CYP3A activities determined with different doses of midazolam in cancer and noncancer Asian patients showed variability of 4-5-fold and were not different between groups. One to two-fold plasma midazolam concentrations per dose may be feasible as a simple alternative phenotypic trait for hepatic CYP3A activity determination.

Adolescent↗
PubMed2000

Is intranasal midazolam an effective rescue medication in adolescents and adults with severe epilepsy?

The aim of this study was to determine whether intranasal midazolam is a safe and effective rescue medication in adolescent and adult patients with severe epilepsy. This field trial was designed to test the feasibility of the use of intranasal midazolam as an alternative to rectal diazepam in a cohort of patients with severe epilepsy who require rescue medication as part of their treatment. A dose of intranasal midazolam (5 mg if the patient weighed less than 50 kg and 10 mg if the patient weighed over 50 kilograms) was prescribed for those who had previously responded to other rescue medication. Midazolam was prescribed buccally if excessive head movement accompanied seizures. The protocol reverted to the usual rescue medication if there was no response to midazolam within 10 minutes. Vital signs were monitored for half an hour following the administration of the treatment. Twenty-two patients received 84 treatment episodes and 79 of these were considered clinically effective. Five treatment failures were recorded, three due to poor technique in delivering the midazolam. Two patients were successfully retried on midazolam and a third is awaiting a retrial of this drug. The two other treatment failures received the drug buccally. In the first patient the clinical opinion was that this was possibly a psychogenic non-epileptic seizure. The other patient responded initially, but within an hour had another seizure requiring further rescue treatment. No significant adverse effects were reported. Our study shows that intranasal midazolam, when used appropriately, is an effective treatment in those who require rescue treatment. There are clear advantages in the use of midazolam over diazepam in the treatment of acute seizures. These include the favourable pharmacokinetic and pharmacodynamic properties of midazolam as well as the potential of a more acceptable and dignified administration route.

Administration, Intranasal↗
PubMed2000

Lack of correlation between in vitro and in vivo studies on the effects of tangeretin and tangerine juice on midazolam hydroxylation.

BACKGROUND: Tangeretin is a flavonoid that stimulates the catalytic activity of cytochrome P450 3A4 (CYP3A4) and is found in high levels in tangerine juice. METHODS: The effect of tangeretin on hydroxylation of midazolam, a CYP3A4 probe, was examined in vitro with human liver microsomes and recombinant CYP3A4. In addition, the effect of tangerine juice on the pharmacokinetics and pharmacodynamics of orally administered midazolam (15 mg) and its active 1'-hydroxymetabolite was studied in a randomized crossover study in eight healthy volunteers. RESULTS: In microsomes from three human livers, tangeretin (1 to 100 micromol/L) increased 1'-hydroxymidazolam formation (12.5 micromol/L midazolam) by up to 212%. In complementary deoxyribonucleic acid-expressed CYP3A4, a 52% stimulation of midazolam 1'-hydroxylation was reached at 50 micromol/L tangeretin with no effect on midazolam 4-hydroxylation. In the pharmacokinetic-pharmacodynamic study, 200 mL tangerine juice reduced the area under the concentration versus time curve to 1.5 hours [AUC(O-1.5h)] of midazolam and 1'-hydroxymidazolam by 39% and 46%, respectively, and prolonged the time to reach peak concentration (P < .05) without affecting the total AUC values, elimination half-life values, or AUC ratios (1'-hydroxymidazolam/midazolam). These findings are consistent with a small delay in the absorption of midazolam and lack of effect on midazolam 1'-hydroxylation. Accordingly, tangerine juice slightly postponed the maximum pharmacodynamic effects of midazolam (P < .05). CONCLUSION: Tangeretin is a potent regioselective stimulator of midazolam 1'-hydroxylation by human liver microsomes and complementary deoxyribonucleic acid-expressed CYP3A4. However, tangerine juice is unlikely to have any appreciable effect on CYP3A4 in humans. Further studies are required to assess whether in vitro stimulators of CYP3A4 can influence drug metabolism in vivo.

Adult↗
PubMed2000

Physostigmine reversal of midazolam-induced electroencephalographic changes in healthy subjects.

OBJECTIVE: Midazolam is a water-soluble benzodiazepine. Flumazenil is a potent antagonist of midazolam-induced sedation. Physostigmine has also been shown to reverse benzodiazepine sedation in anecdotal reports. The aim of this study was to quantitatively characterize the reversal of midazolam-induced changes in electroencephalogram (EEG) by physostigmine compared to flumazenil and placebo. METHODS: Twelve healthy male subjects received 5 mg midazolam as an intravenous infusion over 15 minutes. Fifteen minutes after the end of infusion, single doses of either 0.4 mg flumazenil, 0.5 mg physostigmine, or placebo (physiologic saline solution) were administered as intravenous injections in a randomized crossover fashion. Midazolam serum concentrations were measured using liquid chromatography-tandem mass spectrometry. The time from the start of injection until awakening was noted and the EEG was measured. RESULTS: Four subjects were excluded from further pharmacokinetic and pharmacodynamic analysis because no midazolam-induced changes on EEG alpha power could be observed in each of the three study periods. The pharmacokinetics of midazolam were not influenced by flumazenil or physostigmine. Midazolam induced a decrease in EEG alpha power (7.50 to 11.25 Hz) compared with baseline (P < .05). After injection of flumazenil and physostigmine, an increase in EEG alpha power was observed, whereas placebo did not affect alpha power. Subjects opened their eyes 25.2 +/- 1.1 minutes after the placebo injection was begun, whereas subjects awoke after 6.2 +/- 2.7 minutes and 15.4 +/- 3.4 minutes after they received flumazenil and physostigmine, respectively (mean +/- SEM; P < .001). CONCLUSION: Physostigmine and flumazenil antagonized midazolam-induced sedation. This suggests that a reversible central anticholinergic mechanism may be involved in the sedative action of midazolam.

Adult↗
PubMed2002

Flumazenil reduces midazolam-induced cognitive impairment without altering pharmacokinetics.

OBJECTIVES: Intravenous midazolam is used as an in vivo biomarker of hepatic cytochrome P450 (CYP) 3A activity. Midazolam is a central nervous system depressant and can produce cognitive impairment. The purpose of this study was 2-fold: (1) to determine whether administration of intravenous flumazenil given before intravenous midazolam minimizes cognitive impairment and (2) to determine whether flumazenil pretreatment has an effect on midazolam pharmacokinetics during hepatic CYP3A phenotyping. METHODS: Eleven healthy subjects (8 men) received intravenous flumazenil (0.005 mg/kg) or placebo followed 7 minutes later by intravenous midazolam (0.025 mg/kg) in a randomized, double-blind crossover study. Plasma midazolam concentrations were obtained before dosing and at 5, 30, 60, 120, 240, 300, and 360 minutes after dosing and were assayed by liquid chromatography-tandem mass spectrometry. Midazolam pharmacokinetics were determined by noncompartmental methods. The two 1-sided tests procedure was used to compare area under the curve (AUC) between study phases. Data were log-transformed before analysis, and bioequivalence criteria were applied. Digit symbol substitution tests, performed before dosing and at 5, 30, 60, 120, 240, 300, and 360 minutes after dosing, were used to measure cognition. General linear modeling was used to compare scores between study phases. RESULTS: Midazolam AUC extrapolated to infinity [AUC(0-infinity)] between phases was bioequivalent. The AUC ratio (flumazenil plus midazolam/midazolam) was 0.99, with a 90% confidence interval of 0.98 to 1.00. Statistically significant differences(P <or=.05) in digit symbol substitution test scores between phases were determined relative to time and a phase-by-time interaction. CONCLUSIONS: Flumazenil minimizes midazolam-induced cognitive impairment without influencing midazolam pharmacokinetics. However, the risk of side effects (ie, panic attack) caused by flumazenil should be thoroughly considered before implementation of this drug combination during phenotyping in healthy subjects.

Adult↗
PubMed2005

Assessment of the hepatic and intestinal first-pass metabolism of midazolam in a CYP3A drug-drug interaction model rats.

In the current study, to understand the characteristics of dexamethasone (DEX)-treated female rats as an animal model for drug-drug interactions, a double-cannulation method was applied and separately assessed for the intestinal and hepatic first-pass metabolism of midazolam. Midazolam was administered intravenously or orally to the animals, and midazolam concentrations in the portal and systemic plasma were simultaneously determined. Next, the rates of elimination from the intestine and liver were estimated using the AUC values. After oral administration of midazolam, the entire drug was absorbed without intestinal first-pass metabolism, and 93% of the administered midazolam was extracted in the liver of the DEX-treated female rats. Seven per cent of the midazolam administered reached the systemic circulation. When ketoconazole was given orally to the animals, in conjunction with midazolam, the extraction ratio in the liver decreased from 93% to 77% in the control rats, and the bioavailability of midazolam increased to 23%. On the other hand, after intravenous administration, the elimination half-life of midazolam was not changed by ketoconazole pretreatment. These results indicated that midazolam is only extracted in the liver of DEX-treated female rats and that ketoconazole inhibits the hepatic first-pass metabolism, but not the systemic metabolism. In conclusion, DEX-treated female rats can be used as a drug-drug interaction model via CYP3A4 enzyme inhibition, especially for the hepatic first-pass metabolism of orally administered drugs.

Animals↗
PubMed1994

Effects of midazolam and flumazenil on carotid sinus baroreflex control of circulation in rabbits.

We have studied the effects of midazolam and flumazenil on the carotid sinus baroreflex, by examining mean arterial pressure (MAP) and heart rate (HR) responses to partial or complete bilateral carotid occlusion (BCO) in 12 conscious rabbits after aortic denervation. In eight rabbits, the responses to complete BCO were evaluated before and after cumulative doses of midazolam 0.5 and 1.0 mg kg-1, and after flumazenil 0.3 mg kg-1 following administration of midazolam. Midazolam and flumazenil had no effect on MAP or HR before complete BCO and neither affected the MAP response to complete BCO. Midazolam 0.5 and 1.0 mg kg-1 decreased the HR response to 60% and 58% of control, respectively. Flumazenil restored the midazolam-induced depression of the HR response to the control level. In the other four rabbits, we examined the MAP and HR responses to partial BCO (carotid artery pressure reduced by 5, 10 and 20 mm Hg) before and after midazolam 0.5 mg kg-1 and after flumazenil 0.3 mg kg-1 following administration of midazolam. The response to partial occlusion showed the same tendency as the response to complete BCO. These results indicate that midazolam attenuated the HR response of the carotid sinus baroreflex, flumazenil restored this midazolam-induced depression and neither drug affected the MAP response.

Animals↗
PubMed1995

Aging increases pharmacodynamic sensitivity to the hypnotic effects of midazolam.

The effect of aging on the pharmacodynamics of midazolam was investigated in a double-blinded study involving 39 consenting patients ranging in age from 39 to 77 yr. Midazolam was infused intravenously (i.v.) using a pharmacokinetic model-driven drug infusion device to achieve a plasma midazolam concentration that was held constant for the 10-min duration of the study. Blood samples were obtained from the radial artery at 5 and 10 min for subsequent measurement of the plasma midazolam concentrations. With the 10-min sample, the patients were also assessed for the presence or absence of responsiveness to verbal command. To ensure that the pharmacodynamic end-point was assessed under the condition of a relative steady-state effect-site midazolam concentration, only those patients (n = 33) in whom the plasma midazolam concentration at 10 min was within 30% of the measured concentration at 5 min were included in the subsequent data analyses. Logistic regression was used to fit the verbal command response/no response data to a mathematical model that included patient age and the plasma midazolam concentration measured at 10 min. Cp50, the steady-state plasma midazolam concentration at which 50% of patients would be expected not to respond to a specific stimulus (e.g., verbal command), was calculated as a function of age from the parameterized logistic model. The midazolam Cp50 for response to verbal command decreased significantly (P = 0.034) with increasing patient age, demonstrating that aging increases pharmacodynamic sensitivity to the hypnotic effects of midazolam independent of pharmacokinetic factors.

Adult↗
PubMed1991

Plasma concentrations of midazolam in children following intranasal administration.

Nasally administered midazolam appears to be a useful method for rapidly sedating children prior to the induction of anesthesia. We determined the peak plasma concentrations after intranasal administration of midazolam and compared this to plasma concentrations achieved after intravenously administered midazolam in 18 children between the ages of 14 months and 5 yr, who underwent elective closure of an asymptomatic atrial septal or ventricular septal defect. Preanesthetic medication was at the discretion of the attending anesthesiologist. Induction of anesthesia was with halothane in N2O and O2 via mask, and tracheal intubation was performed after the administration of fentanyl or sufentanil plus pancuronium. Anesthesia was maintained with these agents, and augmented with halothane or isoflurane. As soon as arterial access was established, the patient received 0.1 mg/kg of either intranasal or intravenous midazolam. Midazolam concentrations were measured by gas chromatography-mass spectrometry. Intranasal midazolam achieved its peak plasma concentration of 72.2 +/- 27.3 ng/ml in 10.2 +/- 2 min. Ten minutes after the administration of midazolam, the mean plasma concentration in the intranasal midazolam group was 57% of the concentrations in the group receiving midazolam intravenously. These results confirm the clinical impression that intranasal administration of midazolam rapidly achieves sedative plasma concentrations in children.

Administration, Intranasal↗
PubMed1995

Effects of midazolam on intracellular Ca2+ and tension in airway smooth muscles.

BACKGROUND: It has been demonstrated that a group of minor tranquilizers, benzodiazepines, are able to relax airway smooth muscles. To determine the underlying mechanisms of this phenomenon, the effects of midazolam on the intracellular Ca2+ concentration ([Ca2+]i) and tension in airway smooth muscles were investigated. METHODS: Using front-surface fluorometry and fura-2-loaded porcine tracheal smooth muscle strips, both [Ca2+]i and isometric tension developments were simultaneously recorded. RESULTS: When the tracheal strips were exposed to a high external K(+)-solution (40 mM) or 10(-7) M carbachol containing 1.25 mM Ca2+, both [Ca2+]i and tension increased rapidly until they reached a plateau (the steady state). During steady-state contraction induced by K(+)-depolarization or carbachol, the cumulative application of midazolam (10(-7) approximately 10(-4) M) caused decreases in both [Ca2+]i and tension, in a concentration-dependent manner. During 40 mM K(+)-induced depolarization, the stepwise increases in the extracellular Ca2+ concentration induced the stepwise increases in [Ca2+]i and tension. Midazolam (3 x 10(-5) M) inhibited these increases in [Ca2+]i and tension, but had no effect on the [Ca2+]i-tension relationship. In the presence of 3 x 10(-3) M NiCl2 (a nonselective cation channel blocker), midazolam (3 x 10(-5) M) did not cause any additional reduction of [Ca2+]i or tension during the contraction induced by carbachol (10(-7) M). In the absence of extracellular Ca2+, midazolam (3 x 10(-5) M) had no effect on the transient increases in either [Ca2+]i or the tension induced by carbachol (10(-7) M) or caffeine (20 mM). Pretreatment with both 10(-5) M flumazenil (a specific central antagonist of benzodiazepines) and 10(-5) M PK11195 (a specific peripheral antagonist of benzodiazepines) did not influence the effect of 10(-5) M midazolam on [Ca2+]i or tension during the contractions induced by carbachol. CONCLUSIONS: Midazolam directly relaxes airway smooth muscles by decreasing [Ca2+]i; this can be attributed to the inhibition of the influx of extracellular Ca2+. Midazolam has no effect on the release of stored Ca2+. In addition, midazolam has no effect on Ca2+ sensitivity of the contractile apparatus. Finally, benzodiazepine antagonists, flumazenil and PK11195, have no effect on this mechanism of direct action of midazolam on airway smooth muscles.

Animals↗
PubMed1996

Effect of diltiazem on midazolam and alfentanil disposition in patients undergoing coronary artery bypass grafting.

BACKGROUND: Midazolam and alfentanil are desirable anesthetic adjuncts for cardiac anesthesia. They are metabolized by cytochrome P450 3A (CYP3A) enzymes. These isozymes are inhibited by concurrent medications, including the calcium channel antagonist diltiazem, which may have an effect on recovery from anesthesia. METHODS: Thirty patients having coronary artery bypass grafting were randomly assigned to receive either diltiazem (60 mg orally 2 h before induction of anesthesia and an infusion of 0.1 mg.kg-1.h-1 started at induction and continued for 23 h) or placebo in a double-blind study. Anesthesia was induced with 0.1 mg/kg midazolam, 50 micrograms/kg alfentanil, and 20 to 80 mg propofol and maintained with infusions of 1 microgram.kg-1.min-1 of both midazolam and alfentanil supplemented with isoflurane. Plasma midazolam and alfentanil concentrations and areas under the plasma concentration-time curves were determined. The terminal half-life and the time for the drug plasma level to decrease 50% after cessation of the infusion (t50) were calculated for midazolam and alfentanil. Separation from mechanical ventilation and tracheal extubation were performed according to the study protocol. RESULTS: Diltiazem increased the mean concentration-time curves (from end of anesthesia until 23 h) of midazolam by 24% (P < 0.05) and that of alfentanil by 40% (P < 0.05). The mean half-life of midazolam was 43% (P < 0.05) and that of alfentanil was 50% (P < 0.05) longer in patients receiving diltiazem. The mean t50 of alfentanil was 40% longer (P < 0.05) in patients receiving diltiazem, but the change in the mean t50 of midazolam (25%) was not statistically significant. In patients receiving diltiazem, tracheal extubation was performed on average 2.5 h later (P = 0.054) than in those receiving placebo. CONCLUSIONS: Diltiazem slows elimination of midazolam and alfentanil and may delay tracheal extubation after large doses of these anesthetic adjuncts. CYP3A-mediated drug interactions should be considered as confounders when recovery from anesthesia with midazolam and alfentanil infusions is assessed.

Adjuvants, Anesthesia↗
PubMed1998

Population pharmacodynamics of midazolam administered by target controlled infusion in SICU patients after CABG surgery.

BACKGROUND: Midazolam is used commonly for sedation in the surgical intensive care unit. A suboptimal dosing regimen may lead to relative overdosing, which could result in delayed extubation and increased cost. This multicenter trial characterized midazolam pharmacodynamics in patients recovering from coronary artery bypass grafting. METHODS: Three centers enrolled 90 patients undergoing coronary artery bypass grafting. All patients received sufentanil and midazolam via target-controlled infusion. After surgery, midazolam was titrated to a Ramsay sedation score of 5 for 2 h and then decreased to maintain a sedation score of 3 or 4 for at least another 4 h. Pharmacodynamic parameters were derived using NONMEM. The model was cross-validated to test performance. RESULTS: The probability of a given level of sedation was related to the midazolam concentration by this equation: P(Sedation > or = ss) = Cn/(Cn + C(50,ss)n), where ss is the sedation score, C is the sum of the midazolam concentration and a term reflecting the dissipating effect of anesthesia: C = [midazolam] + theta x e(-Kt), where theta = 256 ng/ml and K = 0.19 h(-1). C(50,ss) values for Ramsay scores of 2 to 6 were 5.7, 71, 171, 260, and 659 ng/ml, respectively. The model predicted 57% of the data points correctly and 88% within one sedation score. CONCLUSIONS: Despite previous reports of high interindividual variability in midazolam pharmacodynamics in patients in the surgical intensive care unit, these cross-validation results suggest that, when midazolam is administered using a target-controlled infusion device, the level of sedation can be predicted within 1 sedation score in 88% of patients based on the target midazolam concentration and the time since the conclusion of the anesthetic.

Adult↗
PubMed2002

Mechanisms involved in the antiplatelet activity of midazolam in human platelets.

BACKGROUND: Midazolam is widely used as a sedative and anesthetic induction agent. The aim of this study was to systematically examine the inhibitory mechanisms of midazolam in platelet aggregation. METHODS: The inhibitory mechanisms of midazolam in platelet aggregation were explored by means of analysis of the platelet glycoprotein IIb-IIIa complex, phosphoinositide breakdown, intracellular Ca+2 mobilization, measurement of membrane fluidity, thromboxane B2 formation, and protein kinase C activity. RESULTS: In this study, midazolam dose-dependently (6-26 microm) inhibited platelet aggregation in human platelets stimulated by agonists. Midazolam also dose-dependently inhibited phosphoinositide breakdown and intracellular Ca+2 mobilization in human platelets stimulated by collagen. Midazolam (6-26 mum) significantly inhibited thromboxane A2 formation stimulated by collagen in human platelets. Moreover, midazolam (15 and 26 mum) dose-dependently decreased the fluorescence of platelet membranes tagged with diphenylhexatriene. Rapid phosphorylation of a platelet protein of Mr 47,000 (P47), a marker of protein kinase C activation, was triggered by collagen (2 microg/ml). This phosphorylation was markedly inhibited by midazolam (26 microm). CONCLUSIONS: These results indicate that the antiplatelet activity of midazolam may be involved in the following pathways: the effects of midazolam may initially be caused by induction of conformational changes in platelet membrane, leading to a change in the activity of phospholipase C, and subsequent inhibition of phosphoinositide breakdown and thromboxane A2 formation, thereby leading to inhibition of both intracellular Ca+2 mobilization and phosphorylation of P47 protein.

Blood Platelets↗
PubMed2003

Midazolam stimulates vascular endothelial growth factor release in aortic smooth muscle cells: role of the mitogen-activated protein kinase superfamily.

BACKGROUND: Intravenous anesthetics used during perioperative periods affect the vascular signaling molecules and the vascular reactivity. Vascular endothelial growth factor (VEGF), an angiogenesis factor produced in and secreted from aortic smooth muscle cells, is a specific mitogen for vascular endothelial cells. This study investigated the effects of various intravenous anesthetics on VEGF release, and the underlying mechanism, in a rat aortic smooth muscle cell line, A10 cells. METHODS: Intravenous anesthetics (midazolam and propofol) were continuously administered to rats by infusion. Cultured A10 cells were stimulated by intravenous anesthetics (midazolam, propofol, and ketamine). VEGF was evaluated by immunoassay. The phosphorylation of mitogen-activated protein (MAP) kinases was evaluated by Western blotting. RESULTS: Continuous infusion of midazolam, but not propofol, increased the VEGF concentration in rat plasma. In cultured cells, midazolam stimulated VEGF release, but propofol and ketamine did not. Midazolam induced phosphorylation of p44/p42 MAP kinase and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), without affecting p38 MAP kinase. PD98059 and U0126, specific inhibitors of MAP kinase kinase, significantly reduced the midazolam-stimulated release of VEGF. SP600125, a specific inhibitor of SAPK/JNK, significantly reduced midazolam-stimulated VEGF release. Applied together, PD98059 and SP600125 produced an additive reduction in midazolam-stimulated VEGF release. Moreover, a bolus injection of PD98059 truly inhibited the midazolam-increased VEGF concentration in rat plasma in vivo. CONCLUSIONS: Midazolam, but not propofol or ketamine, stimulates VEGF release in aortic smooth muscle cells. Its effect is mediated at least in part via activation of p44/p42 MAP kinase and SAPK/JNK.

Adjuvants, Anesthesia↗
PubMed1999

Continuous infusions of lorazepam, midazolam, and propofol for sedation of the critically ill surgery trauma patient: a prospective, randomized comparison.

OBJECTIVE: To compare the efficacy, safety, and cost of continuous infusions of lorazepam, midazolam, and propofol in a critically ill trauma/surgery patient population. DESIGN: A prospective, randomized, nonblinded, single center. SETTING: A 16-bed intensive care unit. PATIENTS: A total of 30 ventilated patients who were 18-70 yrs of age and required pharmacologic sedation. Patients with renal and/or liver failure, a history of alcohol abuse, a head injury, or in a coma were excluded. INTERVENTIONS: Patients were randomized by block design to receive lorazepam, midazolam, or propofol. Initial boluses and infusion rates were as follows: lorazepam 0.05 mg/kg, then 0.007 mg/kg/hr; midazolam 0.05 mg/kg, then 0.003 mg/kg/hr; and propofol 0.25 mg/kg, then 0.06 mg/kg/hr. Sedation was assessed and agents titrated every 5-10 mins to achieve > or =2 and <5 on the modified Ramsay scale. Once adequate response was achieved, agents were titrated to maintain the desired level of sedation. MEASUREMENTS AND MAIN RESULTS: Maintenance doses of lorazepam 0.02+/-0.01 mg/kg/hr, midazolam 0.04+/-0.03 mg/kg/hr, and propofol 2.0+/-1.5 mg/kg/hr achieved the desired level of sedation 68%, 79%, and 62% of the time, respectively. Oversedation occurred most often with lorazepam, compared with midazolam and propofol, at 14%, 6%, and 7% of the assessment times, respectively. Undersedation occurred most frequently with propofol compared with lorazepam and midazolam, at 31%, 18%, and 16% of the assessment times, respectively. The mean number of dosage changes per day was 7.8+/-4.3 for lorazepam, 4.4+/-2.9 for midazolam, and 5.6+/-6.0 for propofol (p = .91). Sedation costs per patient day (mean +/- SD) were $48+/-$76 (lorazepam), $182+/-$98 (midazolam), and $273+/-$200 (propofol) (p = .005). The potential savings, if all study patients had received lorazepam, is $14,208 compared with $8,808 if all received midazolam. CONCLUSIONS: The data suggest that lorazepam appears to be a cost-effective choice for sedation; however, oversedation may be problematic. Midazolam is the most titratable drug in our population, avoiding excessive oversedation or undersedation. Trauma patients may respond inadequately to propofol even at higher doses. Lorazepam may be the sedative of choice in critically ill trauma/surgery patients.

Adolescent↗
PubMed1995

Attenuation of midazolam-induced EEG activation in rats by both flumazenil and hyperbaric oxygen.

Sedative doses of benzodiazepines, i.e., midazolam, can cause electroencephalography (EEG) activation, which is reversed by the benzodiazepine antagonist flumazenil. Hyperbaric oxygen (HBO) can cause acute cerebral toxicity with sensory and motor abnormalities, including seizures. Benzodiazepines are also administered for anxiolysis, sedation, and seizure prophylaxis to patients receiving HBO treatments. Because of possible interactions on monitored neuroelectric activity, we decided to evaluate the effects of midazolam on the EEG and cortical somatosensory evoked potentials (CEPs) in rats exposed to HBO, as well as to compare this to the effects of flumazenil. Thirty-six Sprague-Dawley rats were studied. Analog 2-channel and computerized EEG analysis (compressed spectral array with spectral edge, power spectrum, and power bands) and CEPs were monitored. Studies were divided into two phases. In phase 1, after baseline recordings, 16 rats were randomly assigned to receive midazolam, 0.1 mg.kg-1 intravenously, then compression to 1,824 mm Hg of O2 (n = 8), or 1,824 mm Hg of O2 followed by the midazolam (n = 8). In phase 2, after baseline recordings, rats were randomly assigned to four (n = 5) groups: midazolam, 0.1 mg.kg-1 intravenously, then compression to 1,824 mm Hg of O2; midazolam, then flumazenil, 0.05 mg.kg-1 intravenously; compression, then midazolam; or flumazenil, then midazolam. Recordings of EEG and CEPs were compared by analysis of variance and the Student's t test. In phase 1, midazolam first showed EEG activation in six (75%) rats, which was reversed by HBO. The HBO first activated the EEG in two rats (25%); midazolam then given had no effect. The CEPs were not altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics, Intravenous↗
PubMed2001

Use of midazolam urinary metabolic ratios for cytochrome P450 3A (CYP3A) phenotyping.

Midazolam (MDZ) total clearance (ClT) is widely used for cytochrome P450 3A (CYP3A) phenotyping, but requires up to eight blood samples. This study was conducted to compare the use of midazolam ClT to use of a midazolam urinary metabolic ratio for CYP3A phenotyping. Ten male and 10 female subjects received i.v. midazolam 0.025 mg/kg eight times over a 4-month period at approximately 2-week intervals. The first six phenotyping measures were used to estimate baseline CYP3A activity, then subjects received the moderate CYP3A inhibitor fluvoxamine 150 mg/day for the last 4 weeks (two phenotyping visits) of the study. Serial blood samples were obtained for calculation of ClT. Urine was collected for 6 h following each midazolam dose. Midazolam, 1'-hydroxymidazolam (1-OHMDZ), and 4-hydroxymidazolam were measured in plasma and urine by liquid chromatography with tandem mass spectrometry (LC/MS/MS). Analysis of 148 samples from 20 subjects revealed a weak overall correlation between the urinary ratio of 1-OHMDZ/MDZ to midazolam ClT of r(s) = 0.372 (P = 0.0001). There was no correlation when examining either baseline samples or fluvoxamine-inhibited samples alone (r(s) = 0.101, P = 0.289 and r(s) = 0.266, P = 0.123, respectively). The median (range) urinary ratio decreased significantly with fluvoxamine [219 (141-409) versus 127 (50-464); P = 0.005] and to a similar extent to the midazolam ClT (-33.6% versus -42.4%, respectively; P > 0.05). Median urinary recovery of the i.v. midazolam dose varied between 1.4% and 53% and was significantly lower in samples collected while patients were receiving fluvoxamine (34.3% versus 23.1%; P= 0.0004). Based on these results, although this midazolam urinary ratio was not very reflective of baseline CYP3A activity, it may be a useful indicator of CYP3A inhibition.

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