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Korean Journal of Anesthesiology Aug 2022Intravenous anesthetic agents such as midazolam, propofol, and ketamine are routinely used to provide anesthesia and sedation. They have been shown to effectively induce... (Review)
Review
Intravenous anesthetic agents such as midazolam, propofol, and ketamine are routinely used to provide anesthesia and sedation. They have been shown to effectively induce and maintain amnesia, sedation, and hypnosis in various patient groups and clinical settings. However, all anesthetic agents have the potential to cause unwanted side effects such as hemodynamic instability, respiratory depression, or slow recovery due to prolonged post-procedural sedation. Remimazolam, a recently approved benzodiazepine for general anesthesia and procedural sedation in Korea, has been successfully used for these purposes. To date, inconclusive knowledge has been obtained regarding the use of remimazolam in different patient populations and under various surgical conditions. With respect to the specific pharmacokinetic and pharmacodynamic characteristics of remimazolam, the use of remimazolam is expected to increase providing safe general anesthesia and sedation. This review aims to provide an overview of the basic and clinical pharmacology of remimazolam and to compare it with midazolam and propofol.
Topics: Anesthesia, General; Anesthetics, Intravenous; Benzodiazepines; Double-Blind Method; Humans; Hypnotics and Sedatives; Midazolam; Propofol
PubMed: 35585830
DOI: 10.4097/kja.22297 -
Journal of Oral Science Jun 2021Remimazolam is a new ultrashort-acting benzodiazepine with fast onset, quick recovery, and few side effects, such as hypotension and respiratory depression. It is... (Review)
Review
Remimazolam is a new ultrashort-acting benzodiazepine with fast onset, quick recovery, and few side effects, such as hypotension and respiratory depression. It is expected to be safe and effective for a wide range of patients undergoing intravenous sedation for dental procedures. The aim of this literature review was to evaluate clinical and sedation outcomes for remimazolam, including method of administration, level of sedation at the dose required, and clinical adverse events. An electronic literature search of databases was conducted, and eight articles were selected for inclusion in this review. Onset time from drug administration to optimal sedation level was faster for remimazolam (around 1.5-6.4 min) than for midazolam. Recovery time was significantly shorter for remimazolam than for midazolam and propofol. A study comparing various doses of remimazolam with midazolam found no significant difference in safety. Comparison of a remimazolam group with a propofol group showed that incidences of hypotension (13.0% vs 42.9%, respectively) and respiratory depression (1.1% vs 6.9%, respectively) were significantly lower for remimazolam. Remimazolam appears to be an ideal sedative.
Topics: Benzodiazepines; Humans; Hypnotics and Sedatives; Midazolam
PubMed: 34092775
DOI: 10.2334/josnusd.21-0051 -
Dexmedetomidine versus Midazolam in Procedural Sedation. A Systematic Review of Efficacy and Safety.PloS One 2017To systematically review the literature comparing the efficacy and safety of dexmedetomidine and midazolam when used for procedural sedation. (Review)
Review
OBJECTIVES
To systematically review the literature comparing the efficacy and safety of dexmedetomidine and midazolam when used for procedural sedation.
MATERIALS AND METHODS
We searched MEDLINE, EMBASE and COCHRANE for clinical trials comparing dexmedetomidine and midazolam for procedural sedation up to June 20, 2016. Inclusion criteria: clinical trial, human subjects, adult subjects (≥18 years), article written in English, German, French or Dutch, use of study medication for conscious sedation and at least one group receiving dexmedetomidine and one group receiving midazolam. Exclusion criteria: patients in intensive care, pediatric subjects and per protocol use of additional sedative medication other than rescue medication. Outcome measures for efficacy comparison were patient and clinician satisfaction scores and pain scores; outcome measures for safety comparison were hypotension, hypoxia, and circulatory and respiratory complications.
RESULTS
We identified 89 papers, of which 12 satisfied the inclusion and exclusion criteria; 883 patients were included in these studies. Dexmedetomidine was associated with higher patient and operator satisfaction than midazolam. Patients receiving dexmedetomidine experienced less pain and had lower analgesic requirements. Respiratory and hemodynamic safety were similar.
CONCLUSIONS
Dexmedetomidine is a promising alternative to midazolam for use in procedural sedation. Dexmedetomidine provides more comfort during the procedure for the patient and clinician. If carefully titrated, the safety profiles are similar.
Topics: Dexmedetomidine; Hemodynamics; Humans; Hypnotics and Sedatives; Midazolam; Respiration
PubMed: 28107373
DOI: 10.1371/journal.pone.0169525 -
European Journal of Heart Failure Oct 2022Benzodiazepines have been used as safe anxiolytic drugs for decades and some authors have suggested they could be an alternative for morphine for treating acute... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Benzodiazepines have been used as safe anxiolytic drugs for decades and some authors have suggested they could be an alternative for morphine for treating acute cardiogenic pulmonary oedema (ACPE). We compared the efficacy and safety of midazolam and morphine in patients with ACPE.
METHODS AND RESULTS
A randomized, multicentre, open-label, blinded endpoint clinical trial was performed in seven Spanish emergency departments (EDs). Patients >18 years old clinically diagnosed with ACPE and with dyspnoea and anxiety were randomized (1:1) at ED arrival to receive either intravenous midazolam or morphine. Efficacy was assessed by in-hospital all-cause mortality (primary endpoint). Safety was assessed through serious adverse event (SAE) reporting, and the composite endpoint included 30-day mortality and SAE. Analyses were made on an intention-to-treat basis. The trial was stopped early after a planned interim analysis by the safety monitoring committee. At that time, 111 patients had been randomized: 55 to midazolam and 56 to morphine. There were no significant differences in the primary endpoint (in-hospital mortality for midazolam vs. morphine 12.7% vs. 17.9%; risk ratio[RR] 0.71, 95% confidence interval [CI] 0.29-1.74; p = 0.60). SAE were less common with midazolam versus morphine (18.2% vs. 42.9%; RR 0.42, 95% CI 0.22-0.80; p = 0.007), as were the composite endpoint (23.6% vs. 44.6%; RR 0.53, 95% CI 0.30-0.92; p = 0.03).
CONCLUSION
Although the number of patients was too small to draw final conclusions and there were no significant differences in mortality between midazolam and morphine, a significantly higher rate of SAEs was found in the morphine group.
Topics: Humans; Adolescent; Midazolam; Morphine; Pulmonary Edema; Heart Failure; Hospital Mortality
PubMed: 35780488
DOI: 10.1002/ejhf.2602 -
The American Journal of Psychiatry Apr 2018Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVE
Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. The authors tested the acute effect of adjunctive subanesthetic intravenous ketamine on clinically significant suicidal ideation in patients with major depressive disorder.
METHOD
In a randomized clinical trial, adults (N=80) with current major depressive disorder and a score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomly assigned to receive ketamine or midazolam infusion. The primary outcome measure was SSI score 24 hours after infusion (at day 1).
RESULTS
The reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI=2.33, 7.59; Cohen's d=0.75). The proportion of responders (defined as having a reduction ≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio=2.85, 95% CI=1.14, 7.15; number needed to treat=4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate=7.65, 95% CI=1.36, 13.94), and this effect mediated 33.6% of ketamine's effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up.
CONCLUSIONS
Adjunctive ketamine demonstrated a greater reduction in clinically significant suicidal ideation in depressed patients within 24 hours compared with midazolam, partially independently of antidepressant effect.
Topics: Adult; Behavior Rating Scale; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Infusions, Intravenous; Ketamine; Male; Midazolam; Middle Aged; Suicidal Ideation; Suicide; Young Adult; Suicide Prevention
PubMed: 29202655
DOI: 10.1176/appi.ajp.2017.17060647 -
Anesthesia Progress 2017Nitrous oxide and midazolam have been used as sedative agents to decrease fear and anxiety associated with dental procedures. Although these agents have been widely used... (Meta-Analysis)
Meta-Analysis Review
Nitrous oxide and midazolam have been used as sedative agents to decrease fear and anxiety associated with dental procedures. Although these agents have been widely used individually, the combination of the two is also commonly used. Four clinical trials were identified that compared the combination technique with the individual use of the drugs. The standardized mean difference (SMD) for each outcome measure was considered for final analysis. Three studies with 534 participants were included in the final meta-analysis, and the SMD [95% CI] was obtained as -0.15 [-0.32, 0.03] and was not statistically significant for cooperation scores. Two studies reported the dose of midazolam required for inducing sedation in 450 participants, and the pooled estimate of SMD [95% CI] was obtained as -0.29 [-0.48, -0.10] and was significant. Two studies with 450 participants reported the time taken to recover from sedation, and the pooled estimate of SMD [95% CI] was obtained as -0.20 [-0.39, -0.01] and favored the combination technique. To conclude, the combination technique combines the pros and cons of both drugs in causing fewer adverse effects due to midazolam by reducing the total dose and also helps to provide better acceptance of nitrous oxide inhalation.
Topics: Anesthesia, Dental; Conscious Sedation; Humans; Hypnotics and Sedatives; Midazolam; Nitrous Oxide; Outcome Assessment, Health Care
PubMed: 28604098
DOI: 10.2344/anpr-63-03-06 -
Journal of Pharmacokinetics and... Dec 2020CYP3A plays an important role in drug metabolism and, thus, can be a considerable liability for drug-drug interactions. Population pharmacokinetics may be an efficient...
CYP3A plays an important role in drug metabolism and, thus, can be a considerable liability for drug-drug interactions. Population pharmacokinetics may be an efficient tool for detecting such drug-drug interactions. Multiple models have been developed for midazolam, the typical probe substrate for CYP3A activity, but no population pharmacokinetic models have been developed for use with inhibition or induction. The objective of the current analysis was to develop a composite parent-metabolite model for midazolam which could adequately describe CYP3A drug-drug interactions. As an exploratory objective, parameters were assessed for potential cut-points which may allow for determination of drug-drug interactions when a baseline profile is not available. The final interaction model adequately described midazolam and 1'-OH midazolam concentrations for constitutive, inhibited, and induced CYP3A activity. The model showed good internal and external validity, both with full profiles and limited sampling (2, 2.5, 3, and 4 h), and the model predicted parameters were congruent with values found in clinical studies. Assessment of potential cut-points for model predicted parameters to assess drug-drug interaction liability with a single profile suggested that midazolam clearance may reasonably be used to detect inhibition (4.82-16.4 L/h), induction (41.8-88.9 L/h), and no modulation (16.4-41.8 L/h), with sensitivities for potent inhibition and induction of 87.9% and 83.3%, respectively, and a specificity of 98.2% for no modulation. Thus, the current model and cut-points could provide efficient and accurate tools for drug-drug liability detection, both during drug development and in the clinic, following prospective validation in healthy volunteers and patient populations.
Topics: Adult; Area Under Curve; Biological Variation, Population; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Healthy Volunteers; Humans; Male; Metabolic Clearance Rate; Midazolam; Middle Aged; Models, Biological; Sensitivity and Specificity; Young Adult
PubMed: 32772302
DOI: 10.1007/s10928-020-09704-1 -
American Journal of Veterinary Research May 2017OBJECTIVE To determine the pharmacokinetic and pharmacodynamic effects of midazolam following IV and IM administration in sheep. ANIMALS 8 healthy adult rams. PROCEDURES... (Clinical Trial)
Clinical Trial
OBJECTIVE To determine the pharmacokinetic and pharmacodynamic effects of midazolam following IV and IM administration in sheep. ANIMALS 8 healthy adult rams. PROCEDURES Sheep were administered midazolam (0.5 mg/kg) by the IV route and then by the IM route 7 days later in a crossover study. Physiologic and behavioral variables were assessed and blood samples collected for determination of plasma midazolam and 1-hydroxymidazolam (primary midazolam metabolite) concentrations immediately before (baseline) and at predetermined times for 1,440 minutes after midazolam administration. Pharmacokinetic parameters were calculated by compartmental and noncompartmental methods. RESULTS Following IV administration, midazolam was rapidly and extensively distributed and rapidly eliminated; mean ± SD apparent volume of distribution, elimination half-life, clearance, and area under the concentration-time curve were 838 ± 330 mL/kg, 0.79 ± 0.44 hours, 1,272 ± 310 mL/h/kg, and 423 ± 143 h·ng/mL, respectively. Following IM administration, midazolam was rapidly absorbed and bioavailability was high; mean ± SD maximum plasma concentration, time to maximum plasma concentration, area under the concentration-time curve, and bioavailability were 820 ± 268 ng/mL, 0.46 ± 0.26 hours, 1,396 ± 463 h·ng/mL, and 352 ± 148%, respectively. Respiratory rate was transiently decreased from baseline for 15 minutes after IV administration. Times to peak sedation and ataxia after IV administration were less than those after IM administration. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated midazolam was a suitable short-duration sedative for sheep, and IM administration may be a viable alternative when IV administration is not possible.
Topics: Administration, Intravenous; Animals; Biological Availability; Cross-Over Studies; Half-Life; Hypnotics and Sedatives; Injections, Intramuscular; Male; Midazolam; Respiratory Rate; Sheep
PubMed: 28441044
DOI: 10.2460/ajvr.78.5.539 -
Epilepsia Jun 2015This review summarizes the therapeutic potential of midazolam as an anticonvulsant antidote for organophosphate (OP) intoxication. (Review)
Review
OBJECTIVE
This review summarizes the therapeutic potential of midazolam as an anticonvulsant antidote for organophosphate (OP) intoxication.
METHODS
Benzodiazepines are widely used to treat acute seizures and status epilepticus (SE), a neurologic emergency of persistent seizures that can lead to severe neuronal damage or death. Midazolam is a benzodiazepine hypnotic with a rapid onset and short duration of action.
RESULTS
Midazolam is considered the new drug of choice for persistent acute seizures and SE, including those caused by neurotoxic OPs and nerve agents. Midazolam is a positive allosteric modulator of synaptic γ-aminobutyric acid (GABA)A receptors in the brain. It potentiates GABAergic inhibition and thereby controls hyperexcitability and seizures. Midazolam is administered intravenously or intramuscularly to control acute seizures and SE. Due to its favorable pharmacokinetic features, midazolam is being considered as a replacement anticonvulsant for diazepam in the antidote kit for nerve agents. Clinical studies such as the recent Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) trial have confirmed the anticonvulsant efficacy of midazolam in SE in prehospital settings.
SIGNIFICANCE
In experimental models, midazolam is effective when given at the onset of seizures caused by nerve agents. However, benzodiazepines are less effective at terminating seizures when given 30 min or later after OP exposure or seizure onset, likely because of internalization or downregulation of synaptic, but not extrasynaptic, GABAA receptors, which can lead to diminished potency and seizure recurrence.
Topics: Animals; Anticonvulsants; Epilepsy; Humans; Midazolam; Organophosphate Poisoning
PubMed: 26032507
DOI: 10.1111/epi.12989 -
Biomedicine & Pharmacotherapy =... May 2021Midazolam is one of top three drugs used in palliative care. Its use increases in the last days of hospice patients' lives while safe dosage can be challenging....
RATIONALE & OBJECTIVE
Midazolam is one of top three drugs used in palliative care. Its use increases in the last days of hospice patients' lives while safe dosage can be challenging. Equations currently used to estimate glomerular filtration rate, e.g: the Cockroft-Gault (eGFR) and the Modification of Diet in Renal Disease (eGFR) ones, do not generate precise calculations, especially in palliative patients exhibiting variations in body parameters. Our aim was to seek new relationships between mean midazolam (M) and alfahydroxymidazolam (OH-M) concentrations in plasma, and selected biochemical and physiological parameters of palliative patients, to enable optimal midazolam pharmacotherapy.
STUDY DESIGN, PARTICIPANTS AND INTERVENTIONS
The pilot study included 11 Caucasians, aged 42-95, with advanced cancer disease, receiving midazolam in a hospice in-patient unit. We tested correlations among M, BMI, eGFR, midazolam clearance (CL), OH-M, bilirubin (Bil) and blood creatinine concentration (Cr). F test and leave-one out (LOO) validation was applied to verify the correlations' significance and predictive ability.
RESULTS
We found ten statistically significant (p < 0.05) correlations related to midazolam pharmacokinetics and physiological factors. We formulated two equations with high degree of predictive ability, based on the eGFR→CL and the (Bil + BMI × Ln(Cr))→M-(OH-M) correlations. The limitations of the study mainly revolve around its pilot nature and the need to continue testing the results on a bigger population. No funding to disclose.
CONCLUSIONS
The significance of correlations corresponding to the arithmetic expressions confirms that Bil, BMI, Ln(Cr) analyzed simultaneously report a series of processes on which midazolam metabolism depends. Two of ten correlations proposed came close to meet all LOO validation criteria. Current findings can help optimize midazolam treatment in palliative therapy.
Topics: Adult; Aged; Aged, 80 and over; Bilirubin; Biomarkers; Body Mass Index; Creatinine; Drug Dosage Calculations; Drug Monitoring; Female; Glomerular Filtration Rate; Humans; Hypnotics and Sedatives; Male; Midazolam; Middle Aged; Models, Biological; Palliative Care; Pilot Projects; Reproducibility of Results
PubMed: 33550045
DOI: 10.1016/j.biopha.2021.111304