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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 -
BMC Anesthesiology Oct 2023Moderate to deep sedation is required for dental treatment of children with dental anxiety. Midazolam is the most commonly used sedative, whereas intranasal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Moderate to deep sedation is required for dental treatment of children with dental anxiety. Midazolam is the most commonly used sedative, whereas intranasal dexmedetomidine is increasingly used in pediatric sedation.
OBJECTIVE
The aim of this trial was to compare the sedative efficacy of oral midazolam alone with that of intranasal dexmedetomidine plus oral midazolam during dental treatment of children with dental anxiety.
DESIGN
In total, 83 children (aged 3-12 years) scheduled to undergo dental sedation were randomized to receive oral midazolam (0.5 mg/kg) and intranasal placebo, or oral midazolam (0.5 mg/kg) plus intranasal dexmedetomidine (2 µg/kg). The primary outcome was the rate of successful sedation for dental treatment. Secondary outcomes were the onset time and adverse events during and after treatment. Data analyses involved descriptive statistics and nonparametric tests.
RESULTS
The rate of successful sedation was significantly higher in combination group (P = 0.007), although the sedation onset time was significantly longer in combination group (17.5 ± 2.4 min) than in monotherapy group (15.7 ± 1.8) (P = 0.003). No children required medical intervention or oxygen therapy for hemodynamic disturbances, and the incidences of adverse events had no significant difference between groups (P = 0.660).
CONCLUSION
Combined treatment with oral midazolam (0.5 mg/kg) and intranasal dexmedetomidine (2 µg/kg) is more significantly effective for managing the behavior of non-cooperative children during dental treatment, compared to oral midazolam (0.5 mg/kg) alone. (Chinese Clinical Trial Registry: ChiCTR2100042300) TRIAL REGISTRATION: ChiCTR2100042300, Clinical trial first registration date: 17/01/2021.
Topics: Child; Humans; Midazolam; Dexmedetomidine; Outpatients; Hypnotics and Sedatives; Anesthesia; Administration, Intranasal
PubMed: 37817075
DOI: 10.1186/s12871-023-02289-5 -
Journal of Zoo and Wildlife Medicine :... Mar 2024Sedation, recovery response, and physiologic outcomes were evaluated in five captive reindeer () in Minnesota using a completely reversible immobilization protocol....
Sedation, recovery response, and physiologic outcomes were evaluated in five captive reindeer () in Minnesota using a completely reversible immobilization protocol. Reindeer were immobilized with butorphanol (0.23-0.32 mg/kg), midazolam (0.23-0.32 mg/kg), and medetomidine (0.15 mg/kg) (BMM) via IM dart. Induction time (IT), recumbency time (DT), and recovery time (RT) were recorded. Temperature (T), respiratory rate (RR), pulse rate (PR), pulse oximetry (SpO), arterial blood gas values including oxygen (PaO), and carbon dioxide (PaCO) tensions and lactate (Lac) were recorded preoxygen supplementation and 15 min postoxygen supplementation. Reversal was done using naltrexone (2.3-3.0 mg/kg), flumazenil (0.008-0.01 mg/kg) and atipamezole (0.62-0.78 mg/kg) (NFA) IM, limiting recumbency to 1 h. Median IT, DT, and RT were 5 min, 46 min, and 7 min, respectively. SpO (92 to 99%, = 0.125), PaO (45.5 to 97 mmHg, = 0.25), and PaCO (46.5 to 54.6 mmHg, = 0.25) all increased, whereas Lac (3.02 to 1.93 mmol/L, = 0.25) decreased between baseline and 15 min postoxygen supplementation, without statistical significance. BMM immobilization, and reversal with NFA provided rapid and effective immobilization and recovery, respectively. Oxygen supplementation mitigated hypoxemia in all reindeer.
Topics: Animals; Medetomidine; Midazolam; Butorphanol; Reindeer; Hypnotics and Sedatives; Ketamine; Oxygen; Immobilization; Heart Rate
PubMed: 38453504
DOI: 10.1638/2023-0011 -
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