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British Journal of Anaesthesia Jul 1991
Topics: Child; Cytochrome P-450 Enzyme Inhibitors; Erythromycin; Humans; Midazolam
PubMed: 1859753
DOI: 10.1093/bja/67.1.131-a -
Epilepsy Research Aug 2021In Japan, intravenous (IV) administration of antiepileptic drugs in a healthcare setting is the preferred treatment option that is both licensed and recommended for... (Clinical Trial)
Clinical Trial
A Phase 3 open-label study of the efficacy, safety and pharmacokinetics of buccally administered midazolam hydrochloride for the treatment of status epilepticus in pediatric Japanese subjects.
BACKGROUND
In Japan, intravenous (IV) administration of antiepileptic drugs in a healthcare setting is the preferred treatment option that is both licensed and recommended for initial treatment of status epilepticus (SE). However, prompt conveyance to a healthcare institution and IV access may be difficult in patients experiencing a seizure and so delay treatment. Thus, there is an unmet need for an alternative effective antiepileptic drug with an easier and more rapid mode of administration. In this study we evaluated a midazolam hydrochloride oromucosal solution (MHOS) that can be simply and rapidly administered to patients in SE.
METHODS
A Phase 3, interventional, multicenter, nonrandomized study was conducted in 28 clinical centers in Japan. Pediatric subjects in convulsive SE received treatment with buccal MHOS with dosage based on their age. The primary efficacy outcome was the percentage of subjects with seizure termination within 10 min and a 30-min absence of visible seizure activity from time of administration. Safety evaluations included respiratory depression and the frequency of treatment-emergent adverse events (TEAEs). Pharmacokinetic (PK) profile was also assessed.
RESULTS
The study population comprised 25 subjects with a median age of 2.8 years and median bodyweight of 13.4 kg. The primary efficacy outcome was achieved in 80 % of subjects; 84 % of subjects had seizure resolution within 10 min. Nine subjects experienced a total of 13 TEAEs, and protocol-defined respiratory depression occurred in one subject. Mean maximum plasma midazolam concentration was 78.0 ng/mL, and mean time to peak concentration was 20.5 min, demonstrating that achieving maximum plasma midazolam concentration is not required for seizure cessation.
CONCLUSIONS
The efficacy, safety and pharmacokinetic profile of MHOS in pediatric Japanese subjects was consistent with that observed in non-Japanese populations. Compared to IV treatments, MHOS offers easier administration which may reduce the time to treatment and thereby minimize the sequelae of prolonged seizures.
Topics: Anticonvulsants; Child; Child, Preschool; Diazepam; Humans; Japan; Midazolam; Status Epilepticus
PubMed: 34020149
DOI: 10.1016/j.eplepsyres.2021.106651 -
Revista Medica de Chile Feb 2021Benzodiazepines are used for perioperative conscious sedation. However, its use may be associated with paradoxical reactions. The known risk factors for these reactions...
BACKGROUND
Benzodiazepines are used for perioperative conscious sedation. However, its use may be associated with paradoxical reactions. The known risk factors for these reactions are age, alcohol and drug abuse and psychiatric disorders.
AIM
To assess the incidence and impact of risk factors of paradoxical reactions to midazolam.
MATERIAL AND METHODS
Cross sectional study of 218 patients aged 50 ± 16 years (51% women) scheduled for elective surgical procedures under regional anesthesia and midazolam sedation. The paradoxical reactions were classified according to their severity in three categories.
RESULTS
The incidence of paradoxical reactions to midazolam was 8.3% (95% confidence interval (CI) 5.0-12.7). All were mild and only 28% of the affected patients required pharmacological treatment, none of them flumazenil. A multivariable logistic regression model showed that the variables independently associated with a paradoxical reaction to midazolam were the use of psychoactive medications (Odds Ratio (OR) = 3.4 [1.1-11], p = 0.04, and the dose of midazolam (OR 1.35 [1.03-1.78], p = 0.03.
CONCLUSIONS
The incidence of paradoxical reactions to midazolam was 8,3% and all were mild. Their risk factors are the use of psychoactive medications and the use of higher doses of midazolam.
Topics: Conscious Sedation; Cross-Sectional Studies; Female; Flumazenil; Humans; Hypnotics and Sedatives; Male; Midazolam
PubMed: 34479268
DOI: 10.4067/s0034-98872021000200237 -
Anesthesiology Dec 1993Midazolam, if used with ketamine for induction and maintenance of anesthesia, may attenuate hyperdynamic circulatory effects and prevent undesirable emergenic reactions....
BACKGROUND
Midazolam, if used with ketamine for induction and maintenance of anesthesia, may attenuate hyperdynamic circulatory effects and prevent undesirable emergenic reactions. The nature of the interaction between midazolam and ketamine used for anesthesia induction was studied in female patients.
METHODS
Quantal dose-response curves were determined in 170 female patients for the drugs, individually and in combination. Two endpoints were assessed, loss of response to verbal command (hypnosis) and loss of response to a 5-s transcutaneous tetanus (anesthesia). At the hypnotic endpoint, interactions were analyzed by fitting the data to a mathematical model in which the response was analyzed in terms of the doses of the two drugs, and an additional term was included to describe nonadditive interactions. At the anesthetic endpoint, the decrease in ED50 of ketamine in the presence of midazolam was assessed because dose-related effects could not be demonstrated for midazolam alone.
RESULTS
At the hypnotic endpoint, the ED50s were: 0.15 mg/kg midazolam (95% CIs 0.11-0.38 mg/kg), 0.37 mg/kg ketamine (95% CIs 0.08-0.44 mg/kg), and the combination of 0.086 mg/kg midazolam and 0.27 mg/kg ketamine (95% CIs 0.07/0.22-0.10/0.31 mg/kg), respectively. The hypnotic effects were found to be additive, and there was no evidence of an interaction. At the anesthetic endpoint, the ED50 of ketamine alone was 0.57 mg/kg (95% CIs 0.47-0.69) and the ED50 for ketamine in the presence of midazolam was also 0.57 mg/kg (95% CIs 0.48-0.79); 0.18 mg/kg midazolam was given at this point. Midazolam had no influence on the anesthetic dose of ketamine.
CONCLUSIONS
When using the combination, doses employed should be adjusted according to the depth of central nervous system depression that is required.
Topics: Adolescent; Adult; Anesthesia; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Hypnosis; Ketamine; Midazolam; Receptors, GABA
PubMed: 8267198
DOI: 10.1097/00000542-199312000-00013 -
Epilepsia Open Jun 2023The neurosteroid allopregnanolone (ALLO) is under investigation as a treatment for benzodiazepine-refractory status epilepticus (SE). Here, we assess the cardiopulmonary...
The neurosteroid allopregnanolone (ALLO) is under investigation as a treatment for benzodiazepine-refractory status epilepticus (SE). Here, we assess the cardiopulmonary safety of intravenous ALLO by itself and after a clinically recommended dose of midazolam (MDZ) in two healthy adult beagles. Each dog received ALLO (1 mg/kg, IV), and after a washout period of 2 weeks, each dog was dosed with MDZ (0.2 mg/kg, IV) followed 10 minutes later by ALLO. Behavioral state, vital signs, arterial blood gases, blood chemistries, and plasma ALLO concentrations were monitored for up to 6 hours after dosing. The dogs appeared sleepy but were fully responsive after both treatments. No depression of mean arterial pressure or respiratory rate was noted. Blood gas measurements failed to show evidence of drug-induced acute respiratory acidosis. Estimated maximum plasma ALLO concentrations were in the range of 1500 to 3000 ng/ml. The results indicate that intravenous ALLO can be used safely to treat benzodiazepine-refractory SE, even when administered shortly after a benzodiazepine.
Topics: Dogs; Animals; Midazolam; Pregnanolone; Status Epilepticus; Administration, Intravenous
PubMed: 36919379
DOI: 10.1002/epi4.12723 -
JAMA Network Open Aug 2023Loss of a previously effective response while still using adequate antidepressant treatment occurs in a relatively high proportion of patients with major depressive... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Loss of a previously effective response while still using adequate antidepressant treatment occurs in a relatively high proportion of patients with major depressive disorder (MDD); therefore, there is a need to develop novel effective treatment strategies.
OBJECTIVE
To assess the efficacy and safety of a single subanesthetic dose of esketamine in boosting the efficacy of oral antidepressants for treating fluctuating antidepressant response in MDD.
DESIGN, SETTING, AND PARTICIPANTS
This single-center, double-blind, midazolam-controlled pilot randomized clinical trial was conducted at Beijing Anding Hospital, Capital Medical University in China. The study enrolled participants aged 18 years and older with fluctuating antidepressant response, defined as patients with MDD experiencing fluctuating symptoms after symptom relief and stabilization. Patient recruitment was conducted from August 2021 to January 2022, and participants were followed-up for 6 weeks. Data were analyzed as intention-to-treat from July to September 2022.
INTERVENTIONS
All participants in the esketamine-treated group received intravenous esketamine at 0.2 mg/kg in 40 minutes. Participants in the midazolam control group received intravenous midazolam at 0.045 mg/kg in 40 minutes.
MAIN OUTCOMES AND MEASURES
The primary outcome was the response rate at 2 weeks, defined as a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included response rate at 6 weeks, remission rates at 2 and 6 weeks, and change in MADRS and Clinical Global Impression-Severity score from baseline to 6 weeks; remission was defined by a MADRS score of 10 or lower.
RESULTS
A total of 30 patients (median [IQR] age, 28.0 [24.0-40.0] years; 17 [56.7%] female) were randomized, including 15 patients randomized to midazolam and 15 patients randomized to esketamine; 29 patients completed the study. Response rates at 2 weeks were significantly higher in the esketamine-treated group than in the midazolam control group (10 patients [66.7%] vs 1 patient [6.7%]; P < .001). Participants treated with esketamine experienced significantly greater reduction in MADRS score from baseline to 2 weeks compared with those treated with midazolam (mean [SD] reduction, 15.7 [1.5] vs 3.1 [1.3]; P < .001). No serious adverse events were observed in this trial, and no psychotogenic effects and clinically significant manic symptoms were reported.
CONCLUSIONS AND RELEVANCE
This pilot randomized clinical trial found that a single subanesthetic dose of esketamine could boost the efficacy of oral antidepressants in treating fluctuating antidepressant response, with a good safety profile.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR2100050335.
Topics: Humans; Female; Adult; Male; Depressive Disorder, Major; Midazolam; Pilot Projects; Antidepressive Agents
PubMed: 37578792
DOI: 10.1001/jamanetworkopen.2023.28817 -
Drug Design, Development and Therapy 2018Premedication is the most common way to minimize distress in children entering the operating room and to facilitate the smooth induction of anesthesia and is... (Comparative Study)
Comparative Study
Comparison of oral dexmedetomidine and midazolam for premedication and emergence delirium in children after dental procedures under general anesthesia: a retrospective study.
BACKGROUND
Premedication is the most common way to minimize distress in children entering the operating room and to facilitate the smooth induction of anesthesia and is accomplished using various sedative drugs before the children are being transferred to the operating room. The aim of this study was to compare the effect of oral dexmedetomidine (DEX) and oral midazolam (MID) on preoperative cooperation and emergence delirium (ED) among children who underwent dental procedures at our hospital between 2016 and 2017.
PATIENTS AND METHODS
The medical records of 52 children, who were American Society of Anesthesiologists I, aged between 3 and 7 years, and who underwent full-mouth dental rehabilitation under general anesthesia (GA), were evaluated. Twenty-six patients were given 2 µg/kg of DEX, while another 26 patients were given 0.5 mg/kg of MID in apple juice as premedication agents. The patients' scores on the Ramsay Sedation Scale (RSS), Parental Separation Anxiety Scale (PSAS), Mask Acceptance Scale, Pediatric Anesthesia Emergence Delirium Scale (PAEDS), and hemodynamic parameters were recorded from patients' files. The level of sedation of children had been observed just before premedication and at 15, 30, and 45 min after premedication. The data were analyzed using a chi-square test, Fisher's exact test, Student's -test, and analysis of variance in SPSS.
RESULTS
The Mask Acceptance Scale and PSAS scores and RSS scores at 15, 30, and 45 min after premedication were not statistically different (>0.05) in both groups, whereas the PAEDS scores were significantly lower in the DEX group (<0.05).
CONCLUSION
Oral DEX provided satisfactory sedation levels, ease of parental separation, and mask acceptance in children in a manner similar to MID. Moreover, children premedicated with DEX experienced lesser ED than those premedicated with MID.
Topics: Administration, Oral; Anesthesia, Dental; Child; Child, Preschool; Dexmedetomidine; Emergence Delirium; Female; Humans; Male; Midazolam; Premedication; Retrospective Studies
PubMed: 29636599
DOI: 10.2147/DDDT.S163828 -
Anesthesiology Nov 1990More than 80 deaths have occurred after the use of midazolam (Versed), often in combination with opioids, to sedate patients undergoing various medical and surgical...
More than 80 deaths have occurred after the use of midazolam (Versed), often in combination with opioids, to sedate patients undergoing various medical and surgical procedures. We investigated the respiratory effects of midazolam (0.05 mg.kg-1) and fentanyl (2.0 micrograms.kg-1) in volunteers. The incidence of hypoxemia (oxyhemoglobin saturation less than 90%) and apnea (no spontaneous respiratory effort for 15 s) and the ventilatory response to carbon dioxide were evaluated. Midazolam alone produced no significant respiratory effects. Fentanyl alone produced hypoxemia in half of the subjects and significant depression of the ventilatory response to CO2, but did not produce apnea. Midazolam and fentanyl in combination significantly increased the incidence of hypoxemia (11 of 12 subjects) and apnea (6 of 12 subjects), but did not depress the ventilatory response to CO2 more than did fentanyl alone. Adverse reactions linked to midazolam and reported to the Department of Health and Human Services highlight apnea- and hypoxia-related problems as among the most frequent adverse reactions. Seventy-eight per cent of the deaths associated with midazolam were respiratory in nature, and in 57% an opioid had also been administered. All but three of the deaths associated with the use of midazolam occurred in patients unattended by anesthesia personnel. We conclude that combining midazolam with fentanyl or other opioids produces a potent drug interaction that places patients at a high risk for hypoxemia and apnea. Adequate precautions, including monitoring of patient oxygenation with pulse oximetry, the administration of supplemental oxygen, and the availability of persons skilled in airway management are recommended when benzodiazepines are administered in combination with opioids.
Topics: Adolescent; Adult; Apnea; Carbon Dioxide; Conscious Sedation; Drug Interactions; Drug Therapy, Combination; Fentanyl; Humans; Hypoxia; Male; Midazolam; Respiration
PubMed: 2122773
DOI: 10.1097/00000542-199011000-00005 -
Journal of Pharmaceutical and... Jan 2020Ketamine (Ket) and midazolam (MDZ) are commonly administered drugs in the intensive care setting for analgesia and sedation. Ket and MDZ are metabolized to... (Observational Study)
Observational Study
Simultaneous quantitative LC-MS method of ketamine, midazolam and their metabolites (dehydronorketamine, norketamine and 1hydroxymidazolam) for its application in patients on extracorporeal membrane oxygenation (ECMO) therapy.
Ketamine (Ket) and midazolam (MDZ) are commonly administered drugs in the intensive care setting for analgesia and sedation. Ket and MDZ are metabolized to dehydro-norketamine (DHNK), nor-ketamine (NK) and 1-hydroxy midazolam (1HMDZ). Limited studies evaluating their pharmacokinetics exists in patients on extracorporeal membrane oxygenation (ECMO) therapy. Therefore, we developed a quantitative, high-performance liquid chromatography-mass spectrometry (with single ion monitoring) method to simultaneously detect Ket, MDZ and their (DHNK, NK and 1HMDZ) metabolites in human plasma. Considerable sensitivity was obtained for the analytes using a C HILIC column operated by a high-performance liquid chromatography system coupled with a Thermo Exactive Orbitrap mass spectrometer. Calibration curves were developed for analyte molecules (n = 5) in the presence of carbamazepine (CBZ) as an internal standard. The lower limits of quantitation (LLOQ) for Ket and MDZ were 20 and 10 ng/mL, respectively with the LLOQ for DHNK, NK and 1HMDZ at 470, 320 and 150 ng/ml. Moreover, the percent coefficient of variance and precision for inter- and intra-day runs were within the standards set forth by the ICH and FDA guidelines. This method is sensitive and has been successfully applied to an ongoing pharmacokinetic study in patients on ECMO therapy.
Topics: Amines; Calibration; Chromatography, High Pressure Liquid; Extracorporeal Membrane Oxygenation; Humans; Ketamine; Midazolam; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 31708269
DOI: 10.1016/j.jpba.2019.112947 -
International Journal of Surgery... Jul 2023Severe dental phobia or failure to cooperate with treatment are very common in outpatient pediatric dentistry. Personalized and appropriate noninvasive anesthesia... (Clinical Trial)
Clinical Trial
BACKGROUND
Severe dental phobia or failure to cooperate with treatment are very common in outpatient pediatric dentistry. Personalized and appropriate noninvasive anesthesia methods can save medical expenses, improve treatment efficiency, reduce the anxiety of children, and improve the satisfaction of nursing staff. Currently, there is little conclusive evidence for noninvasive moderate sedation strategies in pediatric dental surgery.
MATERIALS AND METHODS
The trial was conducted from May 2022 to September 2022. Each child was first given midazolam oral solution 0.5 mg·kg -1 , and when the Modified Observer's Assessment of Alertness and Sedation score reached 4, a biased coin design up-down method was used to adjust the dose of esketamine. The primary outcome was the ED 95 and 95% CI of intranasal esketamine hydrochloride with midazolam 0.5 mg·kg -1 . Secondary outcomes included the onset time of sedation, treatment and awakening times, and the incidence of adverse events.
RESULTS
A total of 60 children were enrolled; 53 children were successfully sedated but 7 were not. The ED 95 of intranasal esketamine with 0.5 mg·kg -1 midazolam oral liquid for the treatment of dental caries was 1.99 mg·kg -1 (95% CI 1.95-2.01 mg·kg -1 ). The mean onset time of sedation for all patients was 43.7±6.9 min. 15.0 (10-24.0) min for examination and 89.4±19.5 min for awakening. The incidence of intraoperative nausea and vomiting was 8.3%. Adverse reactions such as transient hypertension and tachycardia occurred during the operations.
CONCLUSION
The ED 95 of intranasal esketamine with 0.5 mg·kg -1 midazolam oral liquid for the outpatient pediatric dentistry procedure under moderate sedation was 1.99 mg·kg -1 . For children aged 2-6 years with dental anxiety who require dental surgery, anesthesiologists may consider using midazolam oral solution combined with esketamine nasal drops for noninvasive sedation after a preoperative anxiety scale evaluation.
Topics: Child; Humans; Anesthesia; Dental Caries; Hypnotics and Sedatives; Midazolam; Outpatients; Prospective Studies
PubMed: 37288546
DOI: 10.1097/JS9.0000000000000340