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Acta Anaesthesiologica Scandinavica Nov 2023Procedural sedation aims to facilitate a successful diagnostic or therapeutic procedure. The pharmacokinetic properties and pharmacodynamic effects need to be taken into... (Review)
Review
BACKGROUND
Procedural sedation aims to facilitate a successful diagnostic or therapeutic procedure. The pharmacokinetic properties and pharmacodynamic effects need to be taken into consideration when choosing the ideal sedative. Midazolam and propofol are frequently employed. However, they are associated with respiratory depression with increasing dosage. Also, midazolam has a potentially unpredictable pharmacodynamic response and propofol may cause hypotension and injection site pain. Remimazolam may provide a superior alternative due to its rapid pharmacodynamic profile and insignificant circulatory effects.
METHODS
This protocol employs the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The review aims to assess the beneficial and harmful clinical effects of remimazolam versus placebo or other sedatives in adult patients requiring sedation in relation to a diagnostic or therapeutic procedure, or due to other circumstances. Three primary outcomes are identified: Sedation success rate, respiratory complications, and hemodynamic complications. Six secondary outcomes are identified: among these are quality of recovery and serious adverse events. All randomized trials are included. The search strategy includes six major biomedical databases. Literature screening and data extraction will be performed independently by two authors. Risk of systemic error will be assessed with Risk of Bias 2 Tool. Risk of random error will be assessed with trial sequential analysis. Heterogeneity will be evaluated by appropriate statistical tests. The certainty of the evidence will be judged using Grading of Recommendations Assessment, Development, and Evaluation. Meta-analysis will be carried out with Rstudio. A "Summary of Findings" table will be presented with our primary and secondary outcome results.
DISCUSSION
The systematic review with up-to-date methodology outlined in this protocol investigates the clinical effects of remimazolam in relation to procedural sedation. The results may guide clinicians in the clinical use of remimazolam.
PubMed: 37580880
DOI: 10.1111/aas.14316 -
Cureus Jul 2023Background Behavioral management techniques are employed for children who are fearful and uncooperative. Pharmacologic sedation and anesthesia are frequently utilized to...
Background Behavioral management techniques are employed for children who are fearful and uncooperative. Pharmacologic sedation and anesthesia are frequently utilized to manage pain and anxiety in pediatric dental patients. Aim To evaluate the intraoperative and postoperative pain levels during dental treatment of children sedated with 1.5 μg/kg intranasal dexmedetomidine, 0.3 mg/kg intranasal midazolam, and nitrous oxide. Materials and methods In this crossover study, 24 children between the ages of five and seven years were randomly assigned to receive intranasal atomized dexmedetomidine, intranasal atomized midazolam, and inhaled nitrous oxide during three different visits. At each visit, a single pulp therapy procedure was conducted after administering the respective sedative agent, and the pain levels were documented. There was a one-week interval between each visit to allow for a washout period. The data were analyzed using IBM SPSS Statistics for Windows, Version 22.0 (Released 2013; IBM Corp, Armonk, NY, United States) using the Wilcoxon signed-rank test and Kruskal-Wallis H test (p < 0.05). Results All three sedative agents were equally effective in controlling postoperative and intraoperative pain. Although there was no statistically significant difference among the groups, clinically, midazolam showed lower intraoperative pain levels (mean 1.78 ± 1.42). Conclusion In pediatric dental patients, intranasal midazolam at a dosage of 0.3 mg/kg and intranasal dexmedetomidine at a dosage of 1.5 μg/kg demonstrate comparable effectiveness to nitrous oxide sedation in pain management. These options serve as effective alternatives for anxious children who may not tolerate nitrous oxide sedation.
PubMed: 37575859
DOI: 10.7759/cureus.41676 -
Journal of Clinical Neurophysiology :... Jul 2024To assess the clinical effectiveness of treating acute seizures with midazolam and lidocaine infusion.
PURPOSE
To assess the clinical effectiveness of treating acute seizures with midazolam and lidocaine infusion.
METHODS
This single-center historical cohort study included 39 term neonates with electrographic seizures who underwent treatment with midazolam (1st line) and lidocaine (2nd line). Therapeutic response was measured using continuous video-EEG monitoring. The EEG measurements included total s eizure burden (minutes), maximum ictal fraction (minutes/hour), and EEG-background (normal/slightly abnormal vs. abnormal). Treatment response was considered good (seizure control with midazolam infusion), intermediate (need to add lidocaine to the control), or no response. Using clinical assessments supplemented by BSID-III and/or ASQ-3 at 2 to 9 years old age, neurodevelopment was classified as normal, borderline, or abnormal.
RESULTS
A good therapeutic response was obtained in 24 neonates, an intermediate response in 15, and no response in any of the neonates. Babies with good response showed lower values in maximum ictal fraction compared with those with intermediate response (95% CI: 5.85-8.64 vs. 9.14-19.14, P = 0.002). Neurodevelopment was considered normal in 24 children, borderline in five, and abnormal in other 10 children. Abnormal neurodevelopment was significantly associated with an abnormal EEG background, maximum ictal fraction >11 minutes, and total s eizure burden >25 minutes (odds ratio 95% CI: 4.74-1708.52, P = 0.003; 1.72-200, P = 0.016; 1.72-142.86, P = 0.026, respectively) but not with the therapeutic response. Serious adverse effects were not recorded.
CONCLUSIONS
This retrospective study suggests that the midazolam/lidocaine association could potentially be efficacious in decreasing seizure burden in term neonates with acute seizures. These results would justify testing the midazolam/lidocaine combination as a first-line treatment for neonatal seizures in future clinical trials.
Topics: Humans; Midazolam; Lidocaine; Seizures; Male; Female; Infant, Newborn; Electroencephalography; Anticonvulsants; Treatment Outcome; Cohort Studies; Child, Preschool; Retrospective Studies; Drug Therapy, Combination; Infant; Child
PubMed: 37099703
DOI: 10.1097/WNP.0000000000001013 -
Frontiers in Pharmacology 2023Vortioxetine is a novel anti-major depression disorder drug with a high safety profile compared with other similar drugs. However, little research has been done on...
Vortioxetine is a novel anti-major depression disorder drug with a high safety profile compared with other similar drugs. However, little research has been done on drug-drug interactions (DDI) about vortioxetine. In this paper, the inhibitory effect of vortioxetine on cytochrome P450 (CYP450) and the type of inhibitory mechanism were investigated in human and rat liver microsomes. We set up an incubation system of 200 μL to measure the metabolism of probe substrates at the present of vortioxetine at 37°C. The concentrations of the metabolites of probe substrates were all measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. It was found no time-dependent inhibition (TDI) of vortioxetine through determination of half-maximal inhibitory concentration (IC) shift values. The enzymes and metabolites involved in this experiment in human and rats were as follows: CYP3A4/CYP3A (midazolam); CYP2B6/CYP2B (bupropion); CYP2D6/CYP2D (dextromethorphan); CYP2C8/CYP2C-1 (amodiaquine); CYP2C9/CYP2C-2 (losartan); and CYP2C19/CYP2C-3 (mephenytoin). We found that vortioxetine competitively inhibited CYP2C19 and CYP2D6 in human liver microsomes (HLMs) with inhibition constant (K) values of 2.17 μM and 9.37 μM, respectively. It was noncompetitive inhibition for CYP3A4 and CYP2C8, and its K values were 7.26 μM and 6.96 μM, respectively. For CYP2B6 and CYP2C9, vortioxetine exhibited the mixed inhibition with K values were 8.55 μM and 4.17 μM, respectively. In RLMs, the type of vortioxetine inhibition was uncompetitive for CYP3A and CYP2D (K = 4.41 and 100.9 μM). The inhibition type was competitive inhibition, including CYP2B and CYP2C-2 (K = 2.87 and 0.12 μM). The inhibition types of CYP2C-1 and CYP2C-3 (K = 39.91 and 4.23 μM) were mixed inhibition and noncompetitive inhibition, respectively. The study of the above mechanism will provide guidance for the safe clinical use of vortioxetine so that the occurrence of DDI can be avoided.
PubMed: 37790811
DOI: 10.3389/fphar.2023.1199548 -
BMJ Supportive & Palliative Care Dec 2023While clinical wisdom has long provided suggested guidance around caring for people who use illicit drugs (referred to as PWUD) at the end of life, there is striking...
BACKGROUND
While clinical wisdom has long provided suggested guidance around caring for people who use illicit drugs (referred to as PWUD) at the end of life, there is striking paucity of empirical evidence underpinning these practices. Understanding medications and doses required to manage symptoms at the end of life is essential to provide effective end-of-life care for these patients. This study aimed to examine the type and dose of medications prescribed to hospitalised patients who use illicit drugs at the end of life, compared with patients without previous or current illicit drug use.
METHOD
A retrospective medical record review was conducted on consecutive patient deaths between 2012 and 2017 at a metropolitan hospital. PWUD were identified using the International Classification of Diseases 10th Revision codes for illicit drug use. Daily dosage of opioids, benzodiazepines and antipsychotics was documented for the last 3 days of life and compared with a matched comparator group.
RESULTS
PWUD patients (n=55) received higher doses of opioids, midazolam and antipsychotics than comparator patients (n=55) for each day, significant for opioids in the last 24 hours (p=0.01). PWUD patients received a significantly higher total opioid dose (median=480.0 mg vs 255.0 mg) and midazolam (median=15.0 mg vs 5.0 mg) (both p<0.05). Rates of dose escalation did not differ.
CONCLUSIONS
Results suggest that PWUD require greater doses of symptom-controlling medications, particularly opioids and midazolam, at the end of life but that rates of dose escalation do not differ greatly. This study provides a foundation for future research to inform clinical guidelines for this cohort of palliative care patients.
Topics: Humans; Illicit Drugs; Midazolam; Retrospective Studies; Terminal Care; Analgesics, Opioid; Substance-Related Disorders; Death
PubMed: 34001548
DOI: 10.1136/bmjspcare-2021-002906 -
Drug Metabolism and Disposition: the... Aug 2023Pediatric physiologically based pharmacokinetics modeling in drug development has grown in the past decade but uncertainty remains regarding ontogeny of some drug...
Use of Developmental Midazolam and 1-Hydroxymidazolam Data with Pediatric Physiologically Based Modeling to Assess Cytochrome P450 3A4 and Uridine Diphosphate Glucuronosyl Transferase 2B4 Ontogeny In Vivo.
Pediatric physiologically based pharmacokinetics modeling in drug development has grown in the past decade but uncertainty remains regarding ontogeny of some drug metabolizing enzymes. In this study, a midazolam and 1-hydroxymidazolam physiologically based pharmacokinetic model (PBPK) model was developed and used to define the ontogeny for hepatic cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyl transferase (UGT) 2B4. Data for model development and pharmacokinetic studies on intravenous midazolam in adults and pediatrics were collated from the literature. The PBPK model was verified in the adult population and then used to compare the performance of two ontogeny profiles for CYP3A4 in terms of parent drug elimination in pediatrics. Four studies also published data on the 1-hydroxymidazolam, and this was used to evaluate the known ontogeny for UGT2B4.For midazolam elimination, the Upreti CYP3A4 ontogeny performed better than Salem; mean error (bias) and mean squared error (precision) were 0.14 and 0.064 compared with 0.69 and 1.21, respectively. For 1-hydroxymidazolam elimination, the Simcyp default ontogeny of UGT2B4 appeared to perform best for studies covering the age range 0.5 to 15.7 years, while for a study in younger ages 0 to 1 years it was the Badee UGT2B4 ontogeny. In preterm neonates, overall expression of UGT appeared to be around 10% of that in adults.Identifying the optimal model of CYP3A4 ontogeny is important for the regulatory use of PBPK. The results for midazolam are conclusive but research about other CYP3A4 metabolized compounds will underpin generalizability of the CYP3A4 ontogeny. UGT2B4 ontogeny is less certain, but this study indicates the most likely scenarios. SIGNIFICANCE STATEMENT: A PBPK model for midazolam and 1-hydroxymidazolam was developed to test various ontogeny scenarios for CYP3A4 and UGT2B4. The CYP3A4 ontogeny of Upreti resulted in more accurate prediction of midazolam CL across nine clinical studies, age range birth to 18 years. 1-Hydroxy midazolam was used as a marker of UGT. The Simcyp default 'no ontogeny' profiles for UGT2B4 performed the best; however, for <1 year of age, there was some evidence of overactivity of this enzyme compared to adults.
Topics: Infant, Newborn; Adult; Child; Humans; Infant; Child, Preschool; Adolescent; Midazolam; Cytochrome P-450 CYP3A; Glucuronosyltransferase; Liver; Models, Biological; Drug Interactions
PubMed: 37169511
DOI: 10.1124/dmd.123.001270 -
Clinical Pharmacology in Drug... May 2024Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was...
Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was evaluated in 2 clinical drug-drug interaction studies. The studies assessed the impact of avacopan on the pharmacokinetics (PK) of CYP3A4 substrates midazolam and simvastatin and CYP2C9 substrate celecoxib, and the influence of CYP3A4 inhibitor itraconazole and inducer rifampin on the PKs of avacopan. The results indicated that twice-daily oral administration of 30 mg of avacopan increased the area under the curve (AUC) of midazolam by 1.81-fold and celecoxib by 1.15-fold when administered without food, and twice-daily oral administration of 30 or 60 mg of avacopan increased the AUC of simvastatin by approximately 2.6-3.5-fold and the AUC of the active metabolite β-hydroxy-simvastatin acid by approximately 1.4-1.7-fold when co-administered with food. Furthermore, the AUC of avacopan increased by approximately 2.19-fold when co-administered with itraconazole and decreased by approximately 13.5-fold when co-administered with rifampin. These findings provide critical insights into the potential drug-drug interactions involving avacopan, which could have significant implications for patient care and treatment planning. (NCT06207682).
Topics: Adult; Female; Humans; Male; Middle Aged; Young Adult; Administration, Oral; Area Under Curve; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Food-Drug Interactions; Healthy Volunteers; Itraconazole; Midazolam; Rifampin; Simvastatin
PubMed: 38423992
DOI: 10.1002/cpdd.1389 -
Oral and Maxillofacial Surgery Dec 2023Pediatric dental surgeries are associated with the emotions of fear, anxiety, and other behavioral disturbances of children that need to be managed. Sedation using drugs... (Meta-Analysis)
Meta-Analysis Review
Systematic review and meta-analysis comparing the efficacy of dexmedetomidine to midazolam as premedication and a sedative agent in pediatric patients undergoing dental procedures.
INTRODUCTION
Pediatric dental surgeries are associated with the emotions of fear, anxiety, and other behavioral disturbances of children that need to be managed. Sedation using drugs like dexmedetomidine (DEX) and midazolam (MID) is a common pharmacological behavior managing technique. We conducted this meta-analysis to evaluate the efficacy of both these drugs in current literature.
METHODOLOGY
A thorough literature search was conducted on PubMed, MEDLINE, Google Scholar, and Cochrane's database for randomized studies that compared sedative efficacy of dexmedetomidine with midazolam in children of 0-15 years of age undergoing dental surgeries. Sedation in children during dental procedure, when used as a premedication, at the time of separation from parents and at the time of mask induction, onset time, duration of anesthesia, and surgery were evaluated. The mean differences (MDs), odds ratio (OR), and their 95% confidence intervals (CIs) were calculated both for continuous and dichotomous outcome data using random-effects model.
RESULTS
Seven studies met out inclusion criteria and were analyzed. Results of premedication with DEX was associated with more anxiolysis (OR=0.29, 95% CI: 0.17-0.52, p=0.0001; I=0%) and at the time of separation from parents (OR=0.36, 95% CI: 0.19-0.69, p=0.002; I=52%) in comparison to MID. No significant differences in results were seen at mask induction (OR=0.63, 95% CI: 0.34-1.18, p=0.15; I=47%) and for sedation in children during dental procedures (OR=0.52, 95% CI: 0.07-3.70, p=0.51; I=72%). Also, there were no significant differences in onset time, duration of anesthesia, and surgery between the two agents.
CONCLUSION
DEX proved to be a better premedicant than MID for pediatric patients. No significant difference in efficacy of both sedative agents was observed in children undergoing dental treatment. More clinical trials need to be conducted to see its efficacy in dental surgeries in children of standardized ages and with standard doses.
Topics: Child; Humans; Midazolam; Dexmedetomidine; Hypnotics and Sedatives; Premedication; Anesthesia, Dental
PubMed: 35759132
DOI: 10.1007/s10006-022-01087-6 -
PloS One 2023The use of dexmedetomidine rather than midazolam may improve ICU outcomes. We summarized the available recent evidence to further verify this conclusion. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The use of dexmedetomidine rather than midazolam may improve ICU outcomes. We summarized the available recent evidence to further verify this conclusion.
METHODS
An electronic search of PubMed, Medline, Embase, Cochrane Library, and Web of Science was conducted. Risk ratios (RR) were used for binary categorical variables, and for continuous variables, weighted mean differences (WMD) were calculated, the effect sizes are expressed as 95% confidence intervals (CI), and trial sequential analysis was performed.
RESULTS
16 randomized controlled trials were enrolled 2035 patients in the study. Dexmedetomidine as opposed to midazolam achieved a shorter length of stay in ICU (MD = -2.25, 95%CI = -2.94, -1.57, p<0.0001), lower risk of delirium (RR = 0.63, 95%CI = 0.50, 0.81, p = 0.0002), and shorter duration of mechanical ventilation (MD = -0.83, 95%CI = -1.24, -0.43, p<0.0001). The association between dexmedetomidine and bradycardia was also found to be significant (RR 2.21, 95%CI 1.31, 3.73, p = 0.003). We found no difference in hypotension (RR = 1.44, 95%CI = 0.87, 2.38, P = 0.16), mortality (RR = 1.02, 95%CI = 0.83, 1.25, P = 0.87), neither in terms of adverse effects requiring intervention, hospital length of stay, or sedation effects.
CONCLUSIONS
Combined with recent evidence, compared with midazolam, dexmedetomidine decreased the risk of delirium, mechanical ventilation, length of stay in the ICU, as well as reduced patient costs. But dexmedetomidine could not reduce mortality and increased the risk of bradycardia.
Topics: Humans; Midazolam; Dexmedetomidine; Respiration, Artificial; Bradycardia; Intensive Care Units; Hypnotics and Sedatives; Delirium
PubMed: 37963140
DOI: 10.1371/journal.pone.0294292 -
British Journal of Anaesthesia Jun 2024Sleep disruption is a common occurrence during medical care and is detrimental to patient recovery. Long-term sedation in the critical care setting is a modifiable...
BACKGROUND
Sleep disruption is a common occurrence during medical care and is detrimental to patient recovery. Long-term sedation in the critical care setting is a modifiable factor that affects sleep, but the impact of different sedative-hypnotics on sleep homeostasis is not clear.
METHODS
We conducted a systematic comparison of the effects of prolonged sedation (8 h) with i.v. and inhalational agents on sleep homeostasis. Adult Sprague-Dawley rats (n=10) received dexmedetomidine or midazolam on separate days. Another group (n=9) received propofol or sevoflurane on separate days. A third group (n=12) received coadministration of dexmedetomidine and sevoflurane. Wakefulness (wake), slow-wave sleep (SWS), and rapid eye movement (REM) sleep were quantified during the 48-h post-sedation period, during which we also assessed wake-associated neural dynamics using two electroencephalographic measures: theta-high gamma phase-amplitude coupling and high gamma weighted phase-lag index.
RESULTS
Dexmedetomidine-, midazolam-, or propofol-induced sedation increased wake and decreased SWS and REM sleep (P<0.0001) during the 48-h post-sedation period. Sevoflurane produced no change in SWS, decreased wake for 3 h, and increased REM sleep for 6 h (P<0.02) post-sedation. Coadministration of dexmedetomidine and sevoflurane induced no change in wake (P>0.05), increased SWS for 3 h, and decreased REM sleep for 9 h (P<0.02) post-sedation. Dexmedetomidine, midazolam, and coadministration of dexmedetomidine with sevoflurane reduced wake-associated phase-amplitude coupling (P≤0.01). All sedatives except sevoflurane decreased wake-associated high gamma weighted phase-lag index (P<0.01).
CONCLUSIONS
In contrast to i.v. drugs, prolonged sevoflurane sedation produced minimal changes in sleep homeostasis and neural dynamics. Further studies are warranted to assess inhalational agents for long-term sedation and sleep homeostasis.
Topics: Animals; Rats, Sprague-Dawley; Sevoflurane; Propofol; Dexmedetomidine; Homeostasis; Hypnotics and Sedatives; Midazolam; Male; Sleep; Rats; Electroencephalography; Anesthetics, Inhalation; Wakefulness
PubMed: 38071152
DOI: 10.1016/j.bja.2023.11.014