Intravenous Administration Of Midazolam Research Articles

Conscious sedation for EUS of the esophagus and stomach: A double-blind, randomized, controlled trial comparing midazolam with placebo

Background: Patients undergoing EUS usually receive intravenously administered sedative medication. A double-blind, prospective, randomized trial was conducted to compare midazolam with a placebo for EUS of the esophagus and stomach and to assess patient tolerance and endoscopic feasibility. Methods: A total of 111 patients were randomized to receive midazolam or a placebo. Patients used a visual analogue scale to score pre-EUS anxiety and tolerance for the procedure. Endoscopists used a visual analogue scale to score ease of echoendoscope introduction and overall patient cooperation. Subsequent to EUS, patients were asked if they were willing to undergo the procedure under the same conditions. Results: The patients' visual analogue scale scores indicated that tolerance for the introduction of the echoendoscope and the procedure overall were both significantly better in the midazolam group. Overall patient tolerance was predicted by sedation ( p < 0.001) and pre-EUS anxiety ( p = 0.024). Endoscopists' visual analogue scale scores showed that ease of echoendoscope introduction was significantly better in the midazolam group. There was no significant difference in overall patient cooperation during the procedure. There were no significant differences in introduction time, total procedure time, or patients' willingness to undergo the procedure under the same conditions. Conclusions: EUS of the esophagus and stomach without intravenous sedation is feasible for endoscopists and patients. Patients prefer intravenous administration of midazolam. Assessment of anxiety before EUS may indicate whether administration of midazolam can improve tolerance for the individual patient. (Gastrointest Endosc 2003;57:842-7.)

Central-nervous side effects of midazolam during transesophageal echocardiography

Background: Midazolam is a broadly used drug that can enhance tolerance to transesophageal echocardiography (TEE) in patients with cardiac conditions. Adverse reactions to midazolam have been described previously. We describe central-nervous side effects in 6 of 104 consecutive patients. Methods: One hundred four patients undergoing TEE-diagnostic procedure were investigated. TEE was performed using a SSA 360 Power Vision ultrasound unit (Toshiba, Tokyo, Japan) and a 5- to 6-MHz probe. Indication for TEE was evaluation of cardiac valves (6), search for cardiac embolism (23), patent foramen ovale or atrial septum defect (20), left ventricular dysfunction (11), aortic dissection (7), and other (37). Midazolam and, if necessary, the benzodiazepine antagonist flumazenil (0.25-0.5 mg) were administered intravenously. Results: The mean cumulative dose of midazolam administered in small fractions was 4.8 ± 2 mg. In 6 of 104 patients (5.7%) clinically significant adverse effects to midazolam occurred. The reactions were aggressiveness, euphoria, depression, and intense hiccups (singultus) despite low doses of midazolam. The severest forms of these adverse effects to midazolam could be successfully treated with intravenous infusion of flumazenil (0.25-0.5 mg intravenously). Conclusion: Adverse effects including aggressive, euphoric, or depressive behavior can occur in a significant proportion (6%) of patients with cardiac conditions undergoing TEE after intravenous administration of midazolam. The administration of the benzodiazepine antagonist flumazenil can reverse the adverse effects to midazolam successfully. (J Am Soc Echocardiogr 2002;15:1297-1300.)

Sedation and monitoring of paediatric patients undergoing open low‐field MRI

The purpose of this study was to determine the need, effectiveness and safety of sedation and monitoring in infants and children in a paediatric open low‐field MRI system. Of 274 patients (median age 9 y) examined, only 74 children (median age 25 mo) needed sedation. Sedation was achieved by intravenous administration of midazolam (0.2 mg/kg) and etomidate (0.2 mg/kg). Mean total doses required were 0.28 and 0.27 mg/kg, respectively. With the exception of eight primarily ventilated patients, all children breathed spontaneously. 02 saturation, arterial blood pressure and ECG were monitored. The low resonance frequency of the MRI system required a specially designed high frequency (HF) shielding of the monitor system to avoid HF artifacts. The overall sedation rate was markedly lower (74/274 = 27%) compared to a control group previously examined in a closed high‐field MRI system (52/111 =47%). This was due to a significant lower need for sedation in patients aged up to 10 y (p≤ 0.0001) in the open MRI unit. General anaesthesia could be avoided in all patients. No significant movement artifacts occurred in any of the MRI examinations and no serious side effects were observed. Conclusions: MRI of children is easier in an open MRI system and with fewer sedations, as in closed high‐field systems. Sedation by a combination of midazolam and etomidate is highly effective and safe. Monitoring devices for high‐field systems may have to be modified for low‐field systems. An in‐hose paediatric MRI unit with an open and special paediatric design is of major advantage for imaging pediatric patients.

Anesthetic management during minimally invasive cardiac surgery with the Port-Access system for closure of atrial septal defect.

a ratio of pulmonary to systemic blood flow (Qp/Qs) of 2.7 6 0.9 and a pulmonary artery mean pressure of 15 6 3mmHg (mean 6 standard deviation) (Table 1). All patients underwent preoperative assessment of the aorta, iliac arteries, and femoral arteries by angiography. The patients were premedicated with oral diazepam (5mg) and intramuscular pethidine (35mg) and atropine (0.5mg). Anesthesia was induced by intravenous administration of midazolam (2 to 4mg), fentanyl (5μg·kg21), and vecuronium (0.15mg·kg21), followed by endotracheal intubation with a standard single-lumen tube. Anesthesia was maintained with sevoflurane and nitrous oxide in oxygen in combination with fentanyl (15 to 20μg·kg21 in total), propofol, and vecuronium. Nitrous oxide was used only before CPB, and propofol was infused continuously during CPB at 4mg·kg21·h21. Intraoperative monitoring included five-lead electrocardiography, pulse oximetry, capnography, urinary output measurement, and nasopharyngeal and bladder temperature. After the induction of anesthesia, the bilateral brachial arteries were cannulated to measure the pressure difference, and a central venous catheter was inserted through the right internal jugular vein. In our institution, we usually use the brachial artery for intravascular blood pressure measurement, since the brachial artery can provide more accurate estimation of aortic pressure than the radial artery [4,5]. Simultaneously, a 5Fr sheath was placed in the right internal jugular vein by the anesthesiologist. A transesophageal echocardiography (TEE) probe was placed. TEE examination was performed to determine the diameter of the ascending aorta and to exclude severe atherosclerosis of the ascending and descending aorta as well as major aortic valve insufficiency. Defibrillator pads were placed over the right lateral and left posterior chest wall. The Port-Access cannulae/catheter-based system (Endovascular CPB system: Heartport) consists of a set

Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole.

The cytochrome P450 3A (CYP3A) isoforms are responsible for the metabolism of a majority of therapeutic compounds, and they are abundant in the intestine and liver. CYP3A activity is highly variable, causing difficulty in the therapeutic use of CYP3A substrates. A practical in vivo probe method that characterizes both intestinal and hepatic CYP3A activity would be useful. To determine the intestinal and hepatic contribution to the bioavailability of midazolam with use of the CYP3A inhibitor ketoconazole. The pharmacokinetics of midazolam was assessed in nine (six men and three women) healthy individuals after single doses of 2 mg intravenous and 6 mg oral midazolam (phase I). These pharmacokinetic values were compared with those obtained after single doses of 2 mg intravenous and 6 mg oral midazolam and three doses of 200 mg oral ketoconazole (phase II). After ketoconazole therapy, area under the concentration versus time curve of midazolam increased 5-fold after intravenous midazolam administration (P < or = .001) and 16-fold after oral midazolam administration (P < or = .001). Intrinsic clearance decreased by 84% (P = .003). Total bioavailability increased from 25% to 80% (P < .001). The intestinal component of midazolam bioavailability increased to a greater extent than the hepatic component (2.3-fold [P = .003] and 1.5-fold [P < or = .001], respectively). In the control phase, female subjects had greater midazolam clearance values than the male subjects. Ketoconazole caused marked inhibition of CYP3A activity that was greater in the intestine than the liver. Administration of single doses of oral and intravenous midazolam with and without oral ketoconazole exemplifies a practical method for differentiating intestinal and hepatic CYP3A activity.

Anesthesia-assisted rapidopiate detoxification: A new procedure in the postanesthesia care unit

Heroin detoxification by anesthesia-assisted rapid opiate detoxification (AAROD) can be achieved in approximately 1 hour using intravenous administration of midazolam, propofol, and naloxone. Opiate dependence and detoxification techniques are reviewed. Important aspects of patient care and perianesthesia nursing are described using a case study. To assist in caring for the patient undergoing anesthesia-assisted rapid opiate detoxification, the perianesthesia nurse should understand the methodology and controversy of this new procedure.

Intravenous midazolam passage into breast milk.

It is desirable to allow breast-feeding as soon as possible after anesthesia. It is common for anesthesiologists to encounter nursing mothers who invariably question whether breast feeding after anesthesia can harm their infants [1]. Only limited reviews concerned with diffusion into breast milk could be found, and in particular there were no studies on breast-feeding after intravenous administration of midazolam to the mother. The present study reports the degree to which intravenously administered midazolam passed from plasma to breast milk in one patient.

Antinociceptive activity of midazolam in sheep.

The purpose of this study was to examine the effects of midazolam on the nociceptive threshold responses in sheep. The intravenous administration of midazolam (0.1-0.3 mg/kg) produced a significant dose-dependent elevation of the mechanical and thermal nociceptive thresholds. The intravenous administration of flumazenil (20 micrograms/kg) markedly attenuated the antinociceptive activity of midazolam in the mechanical nociceptive test, whereas intravenous naloxone (0.2 mg/kg) had no significant effect on midazolam-mediated analgesia. The intrathecal administration of midazolam (1 mg), via chronically implanted cervical subarachnoid catheters, produced a significant elevation in the mechanical threshold responses. These results indicate that midazolam has antinociceptive actions in the sheep and suggest that this effect is, at least partially, mediated at the spinal level.

Experience in Management before, during and after Surgery for a Patient of Mandibular Prognathism with Asthma Attacks

A 23-year-old female with skeletal mandibular prognathism was scheduled for orthognathic surgery. Since she had moderate asthma, consideration was given to avoidance of respiratory complications before, during and after surgery.1. Preoperatively, reversibility of bronchial constriction was evaluated with a spirogram before and after inhalation of a bronchodilator. The patient had been prescribed bronchodilators and bronchodilator aerosols, and antibiotics were administered to prevent postsurgical infections.2. Anesthesia was induced with intravenous administration of midazolam and ketamin. During surgery, the patient was maintained in anesthesia with nitrogen oxide, oxygen and sevoflurane. Aminophyline was administered intravenously to avoid an asthma attack. The patient underwent sagittal split ramus osteotomy. Rigid fixation with titanium screws and intermaxillary traction with elastics after surgery were performed to avoid complications after surgery.3. One day after surgery, despite receiving intravenous aminophylline, this patient had an asthma attack, but it was successfully recovered in fifteen minutes with bronchodilator aerosols after removing the nasogastric tube. Stimulation of the larynx by the nasogastric tube may have induced the attack.4. Orthognathic surgery can be performed on an asthmatic patient if the attending physician is able to prevent asthma attacks or takes proper measures against the occurrence of attacks in close consulation with an asthmatic medical specialist.

Lack off effect of midazolam on inducibility of arrhythmias at electrophysiologic study

Midazolam has several advantages over diazepam as a sedative agent in electrophysiologic studies, but its electrophysiologic effects in humans are unknown. Therefore, its effects were studied in 20 patients undergoing electrophysiologic studies. Electrophysiologic variables were measured before and after administration of intravenous midazolam (5 mg). There were no significant changes in the electrophysiologic variables, apart from a minor decrease in sinus cycle length (711 ± 124 vs 647 ± 91 ms; p = 0.005). Ease of inducibility of reentrant tachycardia was not significantly altered by midazolam, and tachycardia remained inducible in all patients. The drug was well-tolerated with no significant side effects, apart from a minor reduction (mean 18 mm Hg) in blood pressure (p < 0.001). Good amnesic effect was achieved in 16 patients, and most patients preferred it to oral diazepam for sedation during the procedure. It is concluded that midazolam can be used safely in patients undergoing electrophysiologic studies without significantly interfering with electrophysiologic variables or the inducibility of reentrant tachycardias.

Clinical Comparison of Sevoflurane and Isoflurane in Healthy Patients

We compared blood pressure and heart rate changes in healthy patients during anesthesia with sevoflurane (n = 50) versus isoflurane (n = 25) and the rate of recovery after such anesthesia. After premedication with intravenous administration of midazolam, induction of anesthesia with thiopental, and intubation of the trachea facilitated with succinylcholine or vecuronium, anesthesia was maintained with approximately 1 MAC (sevoflurane, 2.05%; isoflurane, 1.15%) of the volatile anesthetic in oxygen for the duration of the operation. Anesthetic concentration was varied as indicated to maintain arterial blood pressure at +/- 20% of baseline values. Sevoflurane and isoflurane produced similar systolic and diastolic arterial blood pressures, but heart rate after incision was faster in patients given isoflurane. Recovery of response to command was shorter in patients given sevoflurane than that in patients given isoflurane (7.5 +/- 0.5 min versus 18.6 +/- 2.0 min). Consistent with this finding, venous blood drawn after anesthesia showed a more rapid initial decay with sevoflurane. Nausea and vomiting were comparable in both groups. We conclude that sevoflurane anesthesia, as compared with isoflurane, is associated with possible advantageous effects on heart rate and recovery.

Matrix attachement sequences improve genetic control of a mammary gland transgene in mice

Cytochrome P450 (CYP) oxidoreductase (POR) is the electron donor for microsomal CYP enzymes. The POR Ala503Val (POR*28 C > T) polymorphism has been reported to influence CYP3A activity in vivo in a white population. The influence of this polymorphism on CYP3A activity in vivo in the Chinese population currently unknown.This study was designed to assess the influence of the POR*28 polymorphism on the CYP3A activity in vivo in healthy Chinese men using midazolam (MID) as a probe drug.The POR*28 polymorphism was genotyped in healthy Chinese men. A randomized, 2-phase, open-label, crossover study was performed to assess in vivo CYP3A activity after both oral and intravenous MID administration, which reflect both intestinal and hepatic CYP3A or only hepatic CYP3A activity, respectively. The plasma concentrations of MID and 1-hydroxy-midazolam (1-OH-MID) were determined by liquid chromatography–tandem mass spectrometry.A total of 73 healthy Chinese men were enrolled (CC genotype, 21 subjects; TT genotype, 11; CT genotype, 41), 22 of whom were selected for additional phenotyping of the CYP3A5*3 polymorphism (CC, 7; TT, 8; CT, 7). The mean (range) age, weight, height, and body mass index of the 22 subjects were 23 (20–28) years, 65.0 (57–75) kg, 1.74 (1.63–1.80) m, and 22.01 (19.27–24.46) kg/m2, respectively. The frequency of the POR*28 T (503V) allele was 43.2%. No significant differences in the demographic characteristics of the subjects were observed between the POR*28 genotype groups. All of the POR*28 CC and TT homozygotes and 2 of the POR*28 CT heterozygotes carried the CYP3A5*3/*3 genotype (CYP3A5 low expressors); 6 CT heterozygotes carried the CYP3A5*1 allele (CYP3A5 expressors). The mean (SD) 1-OH-MID AUC0–8 was significantly greater in the TT homozygotes compared with the CT heterozygotes after intravenous (86.15 [24.34] vs 53.21 [31.36] ng/mL/h; P = 0.026) but not oral (126.36 [31.60] vs 103.09 [31.00] ng/mL/h; P = 0.159) MID administration. Mean 1-OH-MID Cmax was significantly greater in the TT homozygotes (51.40 [10.72] ng/mL) compared with the CC homozygotes (31.47 [11.54] ng/mL; P = 0.002) and CT heterozygotes (30.12 [9.21] ng/mL; P = 0.001) after intravenous MID administration. After intravenous MID injection, the MID metabolic ratio was significantly greater in the TT homozygotes compared with carriers of the C allele (P = 0.031). Based on these findings, no significantly differences in overall (hepatic plus intestinal) CYP3A in vivo activity were observed between the POR*28 genotypes.These findings suggest that individuals with the POR*28 C > T polymorphism underwent an increase in 1-hydroxylation of MID after intravenous MID administration, and that the polymorphism was associated with increased hepatic, but not intestinal, CYP3A activity in these healthy Chinese volunteers.

Gamma-aminobutyric acid type A receptor blockade at the intermediate area of the ventral surface of the medulla counteracts the cardiorespiratory depression produced by intravenous midazolam.

Intravenous administration of midazolam (2 mg/kg) to 8 pentobarbital-anesthetized cats produced a significant decrease in minute ventilation, tidal volume, blood pressure and heart rate. Treatment with the gamma-aminobutyric acid (GABA) type A receptor antagonist bicuculline (10 micrograms/side) at the intermediate area of the ventral surface of the medulla (VSM) oblongata completely reversed the cardiorespiratory depressant effects of intravenous midazolam. In contrast, treatment with bicuculline at the same area failed to counteract the respiratory depressant effects of intravenous morphine (1 mg/kg). We conclude that the cardiorespiratory depressant effects of intravenously administered midazolam are due to enhancement of GABAergic transmission at the intermediate area of the VSM.

Reversible neurologic abnormalities associated with prolonged intravenous midazolam and fentanyl administration

An encephalopathy developed in three infants in the intensive care unit after heavy sedation with midazolam and fentanyl for 4 to 11 days. The affected infants had poor social interaction, decreased visual attentiveness, dystonic postures, and choreoathetosis. Symptoms cleared completely in 5 days to 4 weeks. Retrospective review of records of all children treated in the intensive care unit with prolonged intravenous administration of midazolam revealed that 45 children could be assessed neurologically on withdrawal of sedation. Three children had definite and two had possible neurologic sequelae (5/45, 11.1%). All had received concomitant intravenous fentanyl therapy. Neurologic sequelae were significantly associated with young age, female gender, low serum albumin concentration, and concomitant administration of aminophylline. This encephalopathy may represent a benzodiazepine withdrawal syndrome, a prolonged agonist action on the benzodiazepine receptor, or the combined effects of multiple toxic, metabolic, and infectious insults to the central nervous system of infants in the intensive care unit. Prolonged use of intravenous midazolam sedation necessitates careful dosing, monitoring, and discontinuation, particularly in infants and young children.

Simultaneous determination of midazolam and its three hydroxy metabolites in human plasma by electron-capture gas chromatography without derivatization

Electron-capture gas chromatography was carried out to determine midazolam and its three hydroxy metabolites (1-hydroxymethylmidazolam, 4-hydroxymidazolam and 1-hydroxymethyl-4-hydroxymidazolam) in human plasma. The assay involves extraction from plasma, buffered to pH 9.3, into cyclohexane-dichloromethane (6:4) and analysis by gas chromatography. The use of an HP-17 cross-linked, capillary column makes derivatization unnecessary. The sensitivity of the method was 2–3 ng/ml for midazolam, 1-hydroxymethylmidazolam and 4-hydroxymidazolam, and 20 ng/ml for 1-hydroxymethyl-4-hydroxymidazolam. The extraction recovery of midazolam, 1-hydroxymethylmidazolam, 4-hydroxymidazolam and 1-hydroxymethyl-4-hydroxymidazolam was 99.3±2.4, 67.0±4.6, 92.7±4.7 and 28.7±6.3%, respectively. This gas chromatographic assay was used to assess the concentration-time profiles of midazolam and its metabolites in human plasma after rectal and intravenous administration of midazolam.

Anesthesia for Termination of Pregnancy

Clinical effects of intermittent intravenous administration of midazolam were compared with those of methohexital in two groups of ten premedicated patients each undergoing suction termination of pregnancy under general anesthesia. Both groups received intravenous fentanyl (1 microgram/kg) 5 min prior to administration of the induction agent. No significant difference was found between the two groups in induction time and quality of anesthesia. The recovery time was significantly (17 min) longer in patients who received midazolam (P less than 0.0001).