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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 -
Wideochirurgia I Inne Techniki... Sep 2023Sedation is common during digestive endoscopy to provide comfort and pain relief for patients. However, the use of sedation in endoscopy also poses potential risks, and... (Review)
Review
Sedation is common during digestive endoscopy to provide comfort and pain relief for patients. However, the use of sedation in endoscopy also poses potential risks, and recent issues have been raised regarding its safety and administration. This literature review paper will discuss the most recent developments in the field of sedation in digestive endoscopy, including the adverse events that might be associated with sedation and how to manage it, the legal issues associated with administration, the impact of COVID-19 on sedation practices, and sedation in special situations. It will also touch upon the current guidelines and recommendations for sedation, including the importance of patient selection and monitoring and the need for training and certification for endoscopists administering sedation. The review will also analyse studies evaluating the safety and efficacy of various sedation techniques, including propofol, midazolam, and others. It will examine the benefits and drawbacks of these agents.
PubMed: 37868289
DOI: 10.5114/wiitm.2023.127854 -
British Journal of Clinical Pharmacology Nov 2023To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) and...
AIMS
To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) and dabigatran (a P-glycoprotein substrate).
METHODS
PK was studied in 2 phase 1, open-label, fixed-sequence studies in healthy adults. Single oral doses of midazolam 2 mg (n = 12) or dabigatran 75 mg (n = 24) were administered alone and after steady state (i.e. ≥2 days) of nirmatrelvir/ritonavir 300 mg/100 mg and ritonavir 100 mg. Midazolam and dabigatran plasma concentrations and adverse events were analysed for each treatment.
RESULTS
After administration of midazolam with nirmatrelvir/ritonavir (test) or alone (reference), midazolam geometric mean area under the concentration-time curve extrapolated to infinity (AUC ) and maximum plasma concentration (C ) increased 14.3-fold and 3.7-fold, respectively. Midazolam coadministered with ritonavir (test) or alone (reference) resulted in 16.5-fold and 3.9-fold increases in midazolam geometric mean AUC and C , respectively. After administration of dabigatran with nirmatrelvir/ritonavir (test) or alone (reference), dabigatran geometric mean AUC and C increased 1.9-fold and 2.3-fold, respectively. Dabigatran coadministered with ritonavir (test) or alone (reference) resulted in a 1.7-fold increase in dabigatran geometric mean AUC and C . Midazolam or dabigatran exposures were generally comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, with a slightly higher dabigatran C with nirmatrelvir/ritonavir vs. ritonavir alone. Nirmatrelvir/ritonavir was generally safe when administered with or without midazolam or dabigatran. No serious or severe adverse events were reported.
CONCLUSION
Coadministration of midazolam or dabigatran with nirmatrelvir/ritonavir increased systemic exposure of midazolam or dabigatran. Midazolam exposures were comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, suggesting no incremental effect of nirmatrelvir. Dabigatran C was slightly higher when coadministered with nirmatrelvir/ritonavir compared with of ritonavir alone, suggesting a minor incremental effect of nirmatrelvir.
Topics: Adult; Humans; Midazolam; Ritonavir; Dabigatran; Healthy Volunteers; Drug Interactions; Area Under Curve; Cytochrome P-450 CYP3A
PubMed: 37354048
DOI: 10.1111/bcp.15835 -
Cureus Dec 2023Premedication in anesthesia has long been used to reduce patient anxiety, increase patient compliance, and supplement the overall anesthetic. In pediatric populations,... (Review)
Review
Premedication in anesthesia has long been used to reduce patient anxiety, increase patient compliance, and supplement the overall anesthetic. In pediatric populations, premedication also has the indirect benefits of reducing parental anxiety as well as both the incidence and severity of emergence delirium. Oral midazolam, selected for its ease of administration, short duration of action, and reliable anxiolytic and amnestic effects, has been a favorite choice in this role for decades. The side effect profile of midazolam is also relatively benign, heavily dose-dependent, and easily managed in the perioperative setting. While midazolam appears to be an ideal adjunct in the anesthetic care of pediatric patients, there is a growing body of evidence suggesting prolonged benzodiazepine exposure causes neurodevelopmental changes in infants. This evidence, along with the 2017 Food and Drug Administration (FDA) warning labels for the use of select anesthetic medications, including midazolam in children under the age of three, has led to some debate in the anesthetic community over the continued use of this anesthetic for premedication in pediatric populations. This article aims to educate the reader on the history of midazolam as a premedication agent in pediatric populations and examine the evidence supporting and against its continued use in this role.
PubMed: 38089942
DOI: 10.7759/cureus.50309 -
Journal of Clinical PsychopharmacologyLorazepam is a widely prescribed benzodiazepine that is used to manage anxiety, insomnia, and status epilepticus and is used for pre-anesthetic care as well as several...
BACKGROUND
Lorazepam is a widely prescribed benzodiazepine that is used to manage anxiety, insomnia, and status epilepticus and is used for pre-anesthetic care as well as several off-label indications including aggression, alcohol withdrawal, panic disorder, chemotherapy-associated anticipatory nausea, and catatonia. Recent increases in demand, manufacturing changes, and quality control issues have resulted in a shortage of injectable and oral lorazepam, prompting clinicians to use alternatives. One such alternative is midazolam, a drug that has been used primarily in the intensive care unit and anesthesia settings.
PROCEDURES
This article examines the significant pharmacologic differences between lorazepam and midazolam. In addition, this article provides dosage guidelines based on the current scientific knowledge and recommendations for conversion equivalencies.
RESULTS
The clinical preference for lorazepam can be attributed to its simpler metabolism with no active metabolites, better suitability for patients with less severe hepatic and renal impairment, less risk of adverse reactions, fewer drug-drug interactions, and greater desirability for special populations. In periods of shortages, midazolam has been shown to be effective for a number of off-label uses. To manage conditions that have not been extensively studied, clinicians may opt to use conversion equivalencies, with the caveat that guidelines may vary greatly between institutions and online sources; therefore, it would be best to start low and titrate slowly.
CONCLUSIONS
Our goal is to aid clinicians in safely and effectively prescribing midazolam during the shortage of injectable lorazepam so that patients are provided the same effects and benefits.
Topics: Humans; Lorazepam; Midazolam; Alcoholism; Substance Withdrawal Syndrome; Benzodiazepines
PubMed: 37930205
DOI: 10.1097/JCP.0000000000001763 -
Neurology Nov 2023Early exposure to analgesics and sedatives is a key concern for later learning disorders in children. The hippocampus, a key region for learning and memory, may be...
BACKGROUND AND OBJECTIVES
Early exposure to analgesics and sedatives is a key concern for later learning disorders in children. The hippocampus, a key region for learning and memory, may be selectively affected by exposure to benzodiazepines that are commonly used for sedation, particularly in the neonatal period. In this prospective cohort study, the long-term association of neonatal midazolam exposure, a widely used benzodiazepine in neonatal intensive care, with school age hippocampal growth was examined. Higher-order cognitive function in preterm born children was assessed in relation to hippocampal volumes.
METHODS
Very preterm born children underwent MRI to characterize the hippocampus and its subfields and neuropsychological testing. Generalized linear models were used to determine the predictors of 8-year hippocampal volumes. Children were assessed on the Wechsler Abbreviated Scales of Intelligence, Second Edition, and the Wechsler Intelligence Scales for Children, Fifth Edition (WISC-V).
RESULTS
A total of 140 preterm children who were 8 years of age participated, and 25 (18%) were exposed to midazolam as neonates. Reduced hippocampal volumes at age 8 years were associated with neonatal midazolam exposure (B = -400.2, 95% CI -14.37 to -786.03, = 0.04), adjusting for neonatal clinical care factors. Boys exposed to higher doses of midazolam as neonates had smaller hippocampal volumes (χ = 14.4, = 0.002) compared with nonexposed boys and girls (both, < 0.03). Analysis of the hippocampal subfields in relation to neonatal midazolam dose revealed that higher doses were associated with smaller volumes of the subiculum ( = 0.008), a hippocampal-cortical relay region implicated in memory processes. Furthermore, smaller school age subiculum volumes predicted significantly lower working memory scores on the WISC-V (B = 0.04, 95% CI 0.01-0.07, = 0.017).
DISCUSSION
Early midazolam exposure and the association with impaired hippocampal growth seem long-lasting and are most apparent in boys. Alterations in subiculum volumes may underlie hippocampus-dependent memory formation processes in preterm born children exposed to midazolam as neonates.
Topics: Infant, Newborn; Male; Female; Humans; Child; Midazolam; Memory, Short-Term; Prospective Studies; Hippocampus; Cognition; Benzodiazepines; Magnetic Resonance Imaging
PubMed: 37748888
DOI: 10.1212/WNL.0000000000207817 -
PloS One 2023On July 1st, 2021, the University of Colorado Hospital (UCH) implemented new sedation protocols in the luminal gastrointestinal (GI) suite. GI proceduralist supervised,...
BACKGROUND
On July 1st, 2021, the University of Colorado Hospital (UCH) implemented new sedation protocols in the luminal gastrointestinal (GI) suite. GI proceduralist supervised, Nurse Administered Sedation with fentanyl, midazolam, and diphenhydramine (NAS) sedation was transitioned to Monitored Anesthesia Care with propofol under physician anesthesiologist supervision (MAC).
OBJECTIVE
To determine if there are statistically significant reductions in Sedation-Start to Scope-In time (SSSI) when using Monitored Anesthesia Care with propofol (MAC) versus Nurse Administered Sedation with fentanyl, midazolam, and diphenhydramine (NAS). Secondary objectives were to determine if statistically significant improvements to other operational times, quality measures, and satisfaction metrics were present.
METHOD
This study was a retrospective analysis of a natural experiment resultant of a change from NAS to MAC sedation protocols. Outcomes for NAS protocols from 1/1/21-6/30/21 were compared to outcomes of MAC protocols from the dates 8/1/21-10/31/21. Results were analyzed using Quasi-Poisson regression analysis and stratified based on upper GI, lower GI, and combined procedures. Patient demographic data including age, biological sex, comorbidities, and BMI, were adjusted for in the analysis. ASA matching was not performed as nursing sedation does not use ASA classifications. Pre-anesthesia co-morbidities were assessed via evaluation of a strict set of comorbidities abstracted from the electronic medical record. Perioperative operational outcomes include Sedation Start to Scope-In (SSSI), In-Room to Scope-In Time (IRSI), Scope Out to Out of Room (SOOR), Total Case Length (TCL), and Post Anesthesia Care Unit Length of Stay (PACU LOS). Quality outcomes include PACU Administered Medications (PAM), and Clinician Satisfaction Scores (CSS).
RESULTS
A total of 5,582 gastrointestinal (GI) endoscopic cases (upper, lower, and combined endoscopies) were observed. Statistically significant decreases in SSSI of 2.5, 2.1, and 2.2 minutes for upper, lower, and dual GI procedures were observed when using MAC protocols. A statistically significant increase in satisfaction scores of 47.0 and 19.6 points were observed for nurses and proceduralists, respectively, when using MAC.
CONCLUSION
MAC protocols for endoscopic GI procedures at UCH led to statistically significant decreases in the time required to complete procedures thus increasing operational efficiency.
Topics: Humans; Midazolam; Propofol; Fentanyl; Hypnotics and Sedatives; Diphenhydramine; Retrospective Studies; Colonoscopy; Academic Medical Centers; Anesthesia; Conscious Sedation
PubMed: 38011117
DOI: 10.1371/journal.pone.0294418 -
British Journal of Anaesthesia Mar 2024We aimed to evaluate the comparative effectiveness and safety of various i.v. pharmacologic agents used for procedural sedation and analgesia (PSA) in the emergency... (Meta-Analysis)
Meta-Analysis Review
Pharmacological agents for procedural sedation and analgesia in the emergency department and intensive care unit: a systematic review and network meta-analysis of randomised trials.
BACKGROUND
We aimed to evaluate the comparative effectiveness and safety of various i.v. pharmacologic agents used for procedural sedation and analgesia (PSA) in the emergency department (ED) and ICU. We performed a systematic review and network meta-analysis to enable direct and indirect comparisons between available medications.
METHODS
We searched Medline, EMBASE, Cochrane, and PubMed from inception to 2 March 2023 for RCTs comparing two or more procedural sedation and analgesia medications in all patients (adults and children >30 days of age) requiring emergent procedures in the ED or ICU. We focused on the outcomes of sedation recovery time, patient satisfaction, and adverse events (AEs). We performed frequentist random-effects model network meta-analysis and used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate certainty in estimates.
RESULTS
We included 82 RCTs (8105 patients, 78 conducted in the ED and four in the ICU) of which 52 studies included adults, 23 included children, and seven included both. Compared with midazolam-opioids, recovery time was shorter with propofol (mean difference 16.3 min, 95% confidence interval [CI] 8.4-24.3 fewer minutes; high certainty), and patient satisfaction was better with ketamine-propofol (mean difference 1.5 points, 95% CI 0.3-2.6 points, high certainty). Regarding AEs, compared with midazolam-opioids, respiratory AEs were less frequent with ketamine (relative risk [RR] 0.55, 95% CI 0.32-0.96; high certainty), gastrointestinal AEs were more common with ketamine-midazolam (RR 3.08, 95% CI 1.15-8.27; high certainty), and neurological AEs were more common with ketamine-propofol (RR 3.68, 95% CI 1.08-12.53; high certainty).
CONCLUSION
When considering procedural sedation and analgesia in the ED and ICU, compared with midazolam-opioids, sedation recovery time is shorter with propofol, patient satisfaction is better with ketamine-propofol, and respiratory adverse events are less common with ketamine.
Topics: Adult; Child; Humans; Propofol; Midazolam; Ketamine; Network Meta-Analysis; Pain; Analgesics, Opioid; Analgesia; Emergency Service, Hospital; Intensive Care Units; Conscious Sedation; Randomized Controlled Trials as Topic
PubMed: 38185564
DOI: 10.1016/j.bja.2023.11.050 -
Cureus Dec 2023As benign as its nature is, a febrile seizure (FS) can be one of the most frightening experiences for parents to witness. It is a seizure that occurs in infants and... (Review)
Review
As benign as its nature is, a febrile seizure (FS) can be one of the most frightening experiences for parents to witness. It is a seizure that occurs in infants and children aged six months to five years, accompanied by a fever (with a temperature of at least 100.4°F or 38.0°C by any method), without any infection in the central nervous system. FS is typically benign and tends to resolve on its own. Overall, the risk of recurrence after an FS is high, so there is still a sizable knowledge discrepancy that needs to be addressed for better understanding and management of the disease. Thus, the objective of this review is to evaluate current therapeutic modalities available for FS and summarize recent recommendations on the management of this condition. On June 25, 2023, a review was undertaken using the Medical Subject Headings Tool (MeSH), and the following keywords yielded 867 results: seizures, febrile/drug therapy [Mesh] and seizures, and febrile/therapy [Mesh]. A total of 21 relevant articles were chosen for the research. Seizures were classified as simple and complex FS (CFS) based on clinical features. CFS usually results in recurrence. Certain investigations like computed tomography (CT) scans, magnetic resonance imaging (MRIs), and electroencephalography (EEG) are helpful, along with laboratory investigations, to rule out other causes of FS. After reviewing the current literature, we have tried to conclude whether the current pharmacotherapy is effective in treating FS.
PubMed: 38249234
DOI: 10.7759/cureus.50947 -
Scientific Reports Nov 2023Although remimazolam is an ultra-short-acting benzodiazepine with a shorter elimination half-life and faster recovery time than midazolam, studies evaluating its safety... (Randomized Controlled Trial)
Randomized Controlled Trial
Although remimazolam is an ultra-short-acting benzodiazepine with a shorter elimination half-life and faster recovery time than midazolam, studies evaluating its safety and efficacy during bronchoscopy are limited. This study aimed to compare the safety and efficacy of remimazolam with those of midazolam for bronchoscopy. This prospective randomized parallel-group study was conducted at a single institution. The primary outcome was the time from the end of the procedure to full alertness. Other procedural time parameters, satisfaction profiles, and adverse effects were thoroughly evaluated. The time taken to reach peak sedation and the time from the end of the procedure to full alertness was significantly shorter in the remimazolam group than in the midazolam group (median [interquartile range], 2 min [1-4] vs. 3 min [2-5], P = 0.006; and median, 2 min [1-5] vs. 5 min [1-12], P = 0.035, respectively). In patients with non-biopsy procedures (n = 79), participant satisfaction was significantly higher in the remimazolam group than in the midazolam group (median rated scale, 10 vs. 7, P = 0.042). Physician satisfaction and willingness to repeat the procedure were similar between groups. Although the incidence of adverse effects was similar between the groups and there was no significant difference, the midazolam group had a higher antidote administration rate than the remimazolam group (15.7% vs. 4.1%, P = 0.092). Remimazolam is effective and safe for achieving adequate sedation, with a shorter onset time and faster neuropsychiatric recovery than midazolam. It may be a new option for sedation during bronchoscopy.Trial registration: The trial registration number is NCT05994547, and the date of first registration is 16/08/2023.
Topics: Humans; Midazolam; Hypnotics and Sedatives; Bronchoscopy; Prospective Studies; Double-Blind Method; Benzodiazepines; Drug-Related Side Effects and Adverse Reactions
PubMed: 37993525
DOI: 10.1038/s41598-023-47271-w