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Annals of Neurology Sep 2023Exposure of neonatal macaques to the antiseizure medications phenobarbital and midazolam (PbM) causes widespread apoptotic death of neurons and oligodendrocytes. We...
OBJECTIVE
Exposure of neonatal macaques to the antiseizure medications phenobarbital and midazolam (PbM) causes widespread apoptotic death of neurons and oligodendrocytes. We studied behavior and neurocognitive performance in 12 to 24 month-old macaques treated as neonates with PbM.
METHODS
A total of 14 monkeys received phenobarbital and midazolam over 24 hours under normothermia (n = 8) or mild hypothermia (n = 6). Controls (n = 8) received no treatment. Animals underwent testing in the human intruder paradigm at ages 12 and 18 months, and a 3-step stimulus discrimination task at ages 12, 18, and 24 months.
RESULTS
Animals treated with PbM displayed lower scores for environmental exploration, and higher scores for locomotion and vocalizations compared with controls. Combined PbM and hypothermia resulted in lower scores for aggression and vigilance at 12 months compared with controls and normothermic PbM animals. A mixed-effects generalized linear model was used to test for differences in neurocognitive performance between the control and PbM groups in the first step of the stimulus discrimination task battery (shape center baited to shape center non-baited). The odds of passing this step differed by group (p = 0.044). At any given age, the odds of passing for a control animal were 9.53-fold (95% CI 1.06-85) the odds for a PbM animal. There was also evidence suggesting a higher learning rate in the shape center non-baited for the control relative to the PbM group (Cox model HR 2.13, 95% CI 1.02-4.43; p = 0.044).
INTERPRETATION
These findings demonstrate that a 24-hour-long neonatal treatment with a clinically relevant combination of antiseizure medications can have long-lasting effects on behavior and cognition in nonhuman primates. ANN NEUROL 2023.
PubMed: 37706347
DOI: 10.1002/ana.26794 -
Clinics and Research in Hepatology and... Apr 2024This study aims to perform a meta-analysis to evaluate the safety and efficacy of dexmedetomidine versus midazolam for complex digestive endoscopy procedures, with the... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This study aims to perform a meta-analysis to evaluate the safety and efficacy of dexmedetomidine versus midazolam for complex digestive endoscopy procedures, with the goal of offering comprehensive clinical evidence.
METHODS
Following predefined inclusion criteria, five databases were systematically searched, with a focus on identifying randomized controlled trials (RCTs) that compared the administration of dexmedetomidine and midazolam during complex digestive endoscopy procedures. The statistical software Stata 15.1 was employed for meticulous data analysis.
RESULTS
Sixteen RCTs were encompassed, involving a total of 1218 patients. In comparison to the midazolam group, dexmedetomidine administration was associated with a reduced risk of respiratory depression (RR=0.25, 95 %CI: 0.11-0.56) and hypoxemia (RR=0.22, 95 %CI: 0.12-0.39). Additionally, the dexmedetomidine group exhibited lower incidence rates of choking (RR=0.27, 95 %CI: 0.16-0.47), physical movement (RR=0.16, 95 %CI: 0.09-0.27), and postoperative nausea and vomiting (RR=0.56,95 %CI: 0.34-0.92). Patients and endoscopists in the dexmedetomidine group reported higher levels of satisfaction (patient satisfaction: SMD=0.73, 95 %CI: 0.26-1.21; endoscopist satisfaction: SMD=0.84, 95 %CI: 0.24-1.44). The incidence of hypotension and anesthesia recovery time did not significantly differ between the two groups (hypotension: RR=1.73,95 %CI:0.94-3.20; anesthesia recovery time: SMD=0.02, 95 %Cl: 0.44-0.49). It is noteworthy that the administration of dexmedetomidine was associated with a significant increase in the incidence of bradycardia in patients.
CONCLUSION
Compared to midazolam, dexmedetomidine exhibits a favorable safety profile for use in complex gastrointestinal endoscopy by significantly reducing the risk of respiratory depression and hypoxemia. Despite this, dexmedetomidine is associated with a higher incidence of bradycardia. These findings underscore the need for further research through larger, multi-center studies to thoroughly investigate dexmedetomidine's safety and efficacy.
Topics: Humans; Midazolam; Hypnotics and Sedatives; Dexmedetomidine; Bradycardia; Endoscopy, Gastrointestinal; Respiratory Insufficiency; Hypoxia; Hypotension
PubMed: 38467278
DOI: 10.1016/j.clinre.2024.102315 -
Journal of Zoo and Wildlife Medicine :... Oct 2023Bamboo sharks are some of the most common elasmobranch species in zoos and aquaria and are frequently sedated for medical exams, treatments, and research. This study...
Bamboo sharks are some of the most common elasmobranch species in zoos and aquaria and are frequently sedated for medical exams, treatments, and research. This study investigated the use of an IM sedation protocol of a single dose of dexmedetomidine (0.05 mg/kg) and midazolam (2.0 mg/kg) in brownbanded bamboo sharks (). Sharks were serially monitored every 5 min for heart rate, branchial beats, righting reflex, coelomic response, cloacal response, pelvic fin reflex, response to noxious stimulus, voluntary movement, and ability to swim. This sedation dose was effective at rapidly and significantly decreasing responses to tactile and noxious stimuli with minimal respiratory depression and was quickly reversible with atipamezole (0.5 mg/kg) and flumazenil (0.05 mg/kg). Sedated sharks developed a mild metabolic acidosis evidenced by a significant increase in lactic acid (mean < 0.37 mmol/L presedation, 4.2 mmol/L after reversal) and decrease in blood pH (mean 7.464 presedation, 7.277 after reversal); however, clinical intervention was not required. This protocol should be further investigated in different elasmobranch species but is promising for providing sedation for noninvasive procedures in brownbanded bamboo sharks.
Topics: Animals; Midazolam; Sharks; Dexmedetomidine; Anesthesia
PubMed: 37817610
DOI: 10.1638/2022-0148 -
Medicine Dec 2023A multimodal therapeutic strategy for preventing postoperative nausea and vomiting (PONV) benefits moderate- and high-risk surgical patients. We compared the efficacy of... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparison of the antiemetic efficacy of a combination of midazolam with ramosetron and midazolam with palonosetron for postoperative nausea and vomiting prophylaxis in laparoscopic cholecystectomy.
BACKGROUND
A multimodal therapeutic strategy for preventing postoperative nausea and vomiting (PONV) benefits moderate- and high-risk surgical patients. We compared the efficacy of a combination of midazolam and ramosetron and a combination of midazolam and palonosetron for PONV prophylaxis in patients scheduled for laparoscopic cholecystectomy.
METHODS
We enrolled 68 patients aged 20 to 65 years undergoing laparoscopic cholecystectomy. Patients were randomly allocated to the midazolam 0.05 mg/kg with ramosetron 0.3 mg (MR) or midazolam 0.05 mg/kg with palonosetron 0.075 mg (MP) groups. The incidence of PONV, severity of nausea, use of rescue antiemetics, and pain severity were evaluated at 2, 24, and 48 hours after surgery.
RESULTS
The incidence (38.2% vs 5.9%) and severity of postoperative nausea were significantly lower in the MP group at 2 hours after surgery (P < .05). There were no significant differences in the incidence of vomiting, use of rescue antiemetics, or pain severity between the 2 groups.
CONCLUSION
The combination of midazolam with palonosetron significantly decreased the incidence and severity of postoperative nausea compared with midazolam combined with ramosetron, especially in the early postoperative phase (0-2 hours) in patients undergoing laparoscopic cholecystectomy.
Topics: Humans; Antiemetics; Palonosetron; Postoperative Nausea and Vomiting; Midazolam; Cholecystectomy, Laparoscopic; Double-Blind Method; Benzimidazoles
PubMed: 38206711
DOI: 10.1097/MD.0000000000036824 -
Current Psychiatry Reports Aug 2023The following review will explore ketamine's antidepressant and antisuicidal properties in adults, review of what is known about ketamine's safety in children, and... (Review)
Review
PURPOSE OF REVIEW
The following review will explore ketamine's antidepressant and antisuicidal properties in adults, review of what is known about ketamine's safety in children, and summarize the limited information we have on ketamine's role in treating depression and suicidal ideation in adolescents with depression. Future directions for ketamine's role in child psychiatry based on animal and adult studies will also be explored.
RECENT FINDINGS
Over the past 20 years, ketamine has emerged as a novel treatment for depression and suicidal ideation in adults. In recent years, these studies have been extended to adolescents. In 2021, the first placebo-controlled trial examining ketamine's antidepressant potential in adolescents was performed, demonstrating superior efficacy over midazolam. Initial studies suggest that ketamine functions as a rapidly acting antidepressant in adolescents. Case reports suggest that ketamine may also reduce suicidal ideation in this population. However, existing studies are small, and more research is needed to solidify these findings and inform clinical practice.
Topics: Animals; Child; Humans; Ketamine; Depression; Adolescent Psychiatry; Antidepressive Agents; Suicidal Ideation
PubMed: 37389787
DOI: 10.1007/s11920-023-01432-w -
The Journal of Pharmacy and Pharmacology Jul 2023Delirium (acute brain syndrome) is a common and serious neuropsychiatric disorder characterized by an acute decline in cognitive function. However, there is no effective...
OBJECTIVE
Delirium (acute brain syndrome) is a common and serious neuropsychiatric disorder characterized by an acute decline in cognitive function. However, there is no effective treatment clinically. Here we investigated the potential effect of jujuboside A (JuA, a natural triterpenoid saponin) on cognitive impairment in delirium.
METHODS
Delirium models of mice were established by injecting lipopolysaccharide (LPS) plus midazolam and implementing a jet lag protocol. Novel object recognition test and Y maze test were used to evaluate the effects of JuA on delirium-associated cognitive impairment. The mRNA and protein levels of relevant clock factors and inflammatory factors were measured by qPCR and Western blotting. Hippocampal Iba1+ intensity was determined by immunofluorescence staining.
KEY FINDINGS
JuA ameliorated delirium (particularly delirium-associated cognitive impairment) in mice, which was proved by the behavioural tests, including a preference for new objects, an increase of spontaneous alternation and improvement of locomotor activity. Furthermore, JuA inhibited the expression of ERK1/2, p-p65, TNFα and IL-1β in hippocampus, and repressed microglial activation in delirious mice. This was attributed to the increased expression of E4BP4 (a negative regulator of ERK1/2 cascade and microglial activation). Moreover, loss of E4bp4 in mice abrogated the effects of JuA on delirium as well as on ERK1/2 cascade and microglial activation in the hippocampus of delirious mice. Additionally, JuA treatment increased the expression of E4BP4 and decreased the expression of p-p65, TNFα and IL-1β in LPS-stimulated BV2 cells, supporting a protective effect of JuA on delirium.
CONCLUSIONS
JuA protects against delirium-associated cognitive impairment through promoting hippocampal E4BP4 in mice. Our findings are of great significance to the drug development of JuA against delirium and related disorders.
Topics: Mice; Animals; Tumor Necrosis Factor-alpha; Lipopolysaccharides; Hippocampus; Saponins; Cognition; Delirium; Mice, Inbred C57BL
PubMed: 37330271
DOI: 10.1093/jpp/rgad057 -
Pharmaceutics Nov 2023Midazolam (MDZ) is used for sedation in surgical procedures; its clinical effect is related to its receptor affinity and the dose administered. Therefore, a...
Midazolam (MDZ) is used for sedation in surgical procedures; its clinical effect is related to its receptor affinity and the dose administered. Therefore, a pharmacokinetic-pharmacodynamic (PK-PD) population model of MDZ in pediatric patients undergoing minor surgery is proposed. A descriptive, observational, prospective, and longitudinal, study that included patients of both sexes, aged 2-17 years, ASA I/II, who received MDZ in IV doses (0.05 mg/kg) before surgery. Three blood samples were randomly taken between 5-120 min; both sedation by the Bispectral Index Scale (BIS) and its adverse effects were recorded. The PK-PD relationship was determined using a nonlinear mixed-effects, bicompartmental first-order elimination model using Monolix Suite™. Concentrations and the BIS were fitted to the sigmoid Emax PK-PD population and sigmoid Emax PK/PD indirect binding models, obtaining drug concentrations at the effect site (biophase). The relationship of concentrations and BIS showed a clockwise hysteresis loop, probably indicating time-dependent protein binding. Of note, at half the dose used in pediatric patients, adequate sedation without adverse effects was demonstrated. Further PK-PD studies are needed to optimize dosing schedules and avoid overdosing or possible adverse effects.
PubMed: 38004544
DOI: 10.3390/pharmaceutics15112565 -
Journal of Neuroinflammation Jul 2023Acute exposure to seizurogenic organophosphate (OP) nerve agents (OPNA) such as diisopropylfluorophosphate (DFP) or soman (GD), at high concentrations, induce immediate...
BACKGROUND
Acute exposure to seizurogenic organophosphate (OP) nerve agents (OPNA) such as diisopropylfluorophosphate (DFP) or soman (GD), at high concentrations, induce immediate status epilepticus (SE), reactive gliosis, neurodegeneration, and epileptogenesis as a consequence. Medical countermeasures (MCMs-atropine, oximes, benzodiazepines), if administered in < 20 min of OPNA exposure, can control acute symptoms and mortality. However, MCMs alone are inadequate to prevent OPNA-induced brain injury and behavioral dysfunction in survivors. We have previously shown that OPNA exposure-induced SE increases the production of inducible nitric oxide synthase (iNOS) in glial cells in both short- and long- terms. Treating with a water soluble and highly selective iNOS inhibitor, 1400W, for 3 days significantly reduced OPNA-induced brain changes in those animals that had mild-moderate SE in the rat DFP model. However, such mitigating effects and the mechanisms of 1400W are unknown in a highly volatile nerve agent GD exposure.
METHODS
Mixed-sex cohort of adult Sprague Dawley rats were exposed to GD (132 μg/kg, s.c.) and immediately treated with atropine (2 mg/kg, i.m) and HI-6 (125 mg/kg, i.m.). Severity of seizures were quantified for an hour and treated with midazolam (3 mg/kg, i.m.). An hour post-midazolam, 1400W (20 mg/kg, i.m.) or vehicle was administered daily for 2 weeks. After behavioral testing and EEG acquisition, animals were euthanized at 3.5 months post-GD. Brains were processed for neuroinflammatory and neurodegeneration markers. Serum and CSF were used for nitrooxidative and proinflammatory cytokines assays.
RESULTS
We demonstrate a significant long-term (3.5 months post-soman) disease-modifying effect of 1400W in animals that had severe SE for > 20 min of continuous convulsive seizures. 1400W significantly reduced GD-induced motor and cognitive dysfunction; nitrooxidative stress (nitrite, ROS; increased GSH: GSSG); proinflammatory cytokines in the serum and some in the cerebrospinal fluid (CSF); epileptiform spikes and spontaneously recurring seizures (SRS) in males; reactive gliosis (GFAP + C3 and IBA1 + CD68-positive glia) as a measure of neuroinflammation, and neurodegeneration (especially parvalbumin-positive neurons) in some brain regions.
CONCLUSION
These findings demonstrate the long-term disease-modifying effects of a glial-targeted iNOS inhibitor, 1400W, in a rat GD model by modulating reactive gliosis, neurodegeneration (parvalbumin-positive neurons), and neuronal hyperexcitability.
Topics: Animals; Male; Rats; Atropine; Cytokines; Enzyme Inhibitors; Epilepsy; Gliosis; Midazolam; Neuroglia; Nitric Oxide Synthase Type II; Parvalbumins; Rats, Sprague-Dawley; Seizures; Soman; Status Epilepticus
PubMed: 37438764
DOI: 10.1186/s12974-023-02847-1 -
Trials Nov 2023Preoperative anxiety management is gaining particular attention in paediatric anaesthesia. Pharmacological and non-pharmacological resorts can be implemented to address...
Comparison of S-ketamine and midazolam for intravenous preoperative sedative and anxiolytic effects in preschool children: study protocol for a randomized controlled clinical trial.
BACKGROUND
Preoperative anxiety management is gaining particular attention in paediatric anaesthesia. Pharmacological and non-pharmacological resorts can be implemented to address this special issue. Despite the various approaches currently used for preoperative sedation in children, the different sedative and anti-anxiety effects between the newly marketed anaesthetic, S-ketamine, and the traditional sedative, midazolam, are still unclear.
METHODS
This is a patient- and assessor-blinded randomized controlled clinical trial. Participants (n = 110) will receive S-ketamine (0.5 mg/kg) or midazolam (0.08 mg/kg) intravenously administrated at a ratio of 1:1 in the anaesthesia holding area. The primary outcome of this study is the sedative effect evaluated via the change in the modified Yale preoperative anxiety scale. It will be performed at two timepoints: in the pre-anaesthetic holding area before premedication (baseline, marked as T0) and about 5 min after premedication in the operating room without the existence of their guardians (marked as T1). Our secondary objectives include the parent separation anxiety score, postoperative agitation, caregivers' and anaesthesia care providers' satisfaction, and mask compliance.
DISCUSSION
This randomized controlled trial is the first study to compare the anti-anxiety effect of intravenous S-ketamine and midazolam. We will provide a new approach for the clinical management of preoperative anxiety in preschool children posted for elective surgery.
TRIAL REGISTRATION
ChiCTR2300069998. Registered on 30 March 2023.
Topics: Child, Preschool; Humans; Hypnotics and Sedatives; Midazolam; Anti-Anxiety Agents; Anesthetics; Double-Blind Method; Randomized Controlled Trials as Topic
PubMed: 37957769
DOI: 10.1186/s13063-023-07767-2 -
BMC Anesthesiology Jun 2024Dexmedetomidine and midazolam are commonly used sedatives in children. We conducted a systematic review and meta-analysis to compare the safety and effectiveness of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dexmedetomidine and midazolam are commonly used sedatives in children. We conducted a systematic review and meta-analysis to compare the safety and effectiveness of sedation provided by dexmedetomidine combined with midazolam versus other sedatives including chloral hydrate, midazolam and other sedatives in pediatric sedation.
METHODS
The Embase, Web of Science, Cochrane Library, and PubMed databases, and Clinicaltrials.gov register of controlled trials were searched from inception to June 2022. All randomized controlled trials used dexmedetomidine-midazolam in pediatric sedation were enrolled. The articles search, data extraction, and quality assessment of included studies were performed independently by two researchers. The success rate of sedation was considered as the primary outcome. The secondary outcomes included onset time of sedation, recovery time of sedation and occurrence of adverse events.
RESULTS
A total of 522 studies were screened and 6 RCTs were identified; 859 patients were analyzed. The administration of dexmedetomidine combined with midazolam was associated with a higher sedation success rate and a lower incidence of nausea and vomiting in computed tomography, magnetic resonance imaging, Auditory Brainstem Response test or fiberoptic bronchoscopy examinations than the other sedatives did (OR = 2.92; 95% CI: 1.39-6.13, P = 0.005, I = 51%; OR = 0.23, 95% CI: 0.07-0.68, P = 0.008, I = 0%, respectively). Two groups did not differ significantly in recovery time and the occurrence of adverse reactions (WMD = - 0.27, 95% CI: - 0.93 to - 0.39, P = 0.42; OR 0.70; 95% CI: 0.48-1.02, P = 0.06, I = 45%. respectively). However, the results of the subgroup analysis of ASA I-II children showed a quicker onset time in dexmedetomidine-midazolam group than the other sedatives (WMD=-3.08; 95% CI: -4.66 to - 1.49, P = 0.0001, I = 30%).
CONCLUSIONS
This meta-analysis showed that compared with the control group, dexmedetomidine combined with midazolam group provided higher sedation success rates and caused a lower incidence of nausea and vomiting in completing examinations, indicating a prospective outpatient clinical application for procedural sedation.
Topics: Dexmedetomidine; Humans; Hypnotics and Sedatives; Midazolam; Child; Drug Therapy, Combination; Randomized Controlled Trials as Topic
PubMed: 38907338
DOI: 10.1186/s12871-024-02570-1