-
British Journal of Anaesthesia Apr 2022Anaesthesia and perioperative management contribute to long-term outcomes of patients with cancer, including pancreatic ductal adenocarcinoma. We assessed the...
BACKGROUND
Anaesthesia and perioperative management contribute to long-term outcomes of patients with cancer, including pancreatic ductal adenocarcinoma. We assessed the antitumour, anti-inflammatory, and analgesic effects of midazolam on LSL-Kras;Trp53;Pdx-1 transgenic mice with pancreatic ductal adenocarcinoma.
METHODS
Six-week-old transgenic mice were administered midazolam 30 mg kg day p.o. (n=13); midazolam 30 mg kg day with 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline carboxamide (PK11195) 3 mg kg day i.p., a peripheral benzodiazepine receptor antagonist (n=10); or vehicle (water; n=14) until the humane endpoint. Cancer-associated pain was evaluated using hunching score and mouse grimace scale. Tumour stage and immuno-inflammatory status were determined histopathologically. Anti-proliferative and apoptotic potentials of midazolam were investigated using mouse pancreatic ductal adenocarcinoma cell lines.
RESULTS
Midazolam significantly inhibited tumour size and proliferative index of Ki-67 and cyclins in pancreatic ductal adenocarcinoma, which was blocked by administration of PK11195. Local myeloperoxidase tumour-associated neutrophils, arginase-1 M2-like tumour-associated macrophages, and CD11bLy-6G polymorphonuclear myeloid-derived suppressor cells were reduced by midazolam, which was antagonised by administration of PK11195. Hunching and mouse grimace scale were improved by midazolam, whereas the scores increased with midazolam+PK11195 treatment. Plasma pro-inflammatory cytokines, such as interleukin-6 and CC chemokine ligand (CCL)2, CCL3, and CCL5, were reduced by midazolam, whereas these cytokines increased with PK11195. Midazolam inhibited pancreatic ductal adenocarcinoma proliferation through downregulation of cyclins and cyclin-dependent kinases and induced apoptosis in vitro.
CONCLUSIONS
These results suggest that midazolam inhibits pancreatic ductal adenocarcinoma proliferation and local infiltration of tumour-associated neutrophils, tumour-associated macrophages, and polymorphonuclear myeloid-derived suppressor cells, thereby inhibiting pancreatic ductal adenocarcinoma progression.
Topics: Animals; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Midazolam; Pancreatic Neoplasms
PubMed: 35120712
DOI: 10.1016/j.bja.2021.12.042 -
Anaesthesia Dec 1993A modified patient-controlled analgesia pump provided doses of propofol 3 mg or midazolam 0.1 mg in 0.3 ml, over 5.4 s, with no lockout, during transvaginal oocyte... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
A modified patient-controlled analgesia pump provided doses of propofol 3 mg or midazolam 0.1 mg in 0.3 ml, over 5.4 s, with no lockout, during transvaginal oocyte retrieval. Alfentanil 0.2 mg was administered at three points during the procedure, and on request. Patients were randomly assigned to receive either propofol (25 patients) or midazolam (22 patients). The mean age, weight, duration of procedure and dose of alfentanil were similar in both groups. Onset of sedation with propofol or midazolam took 70.6 (SD 22.4) and 106.3 (50.7) s respectively. Mean doses over the first 5 min were midazolam 2.7 (1.2) mg, and propofol 54 (18) mg. Thereafter requirements decreased: midazolam 0.065 (0.065) mg.min-1, propofol 2.1 (1.3) mg.min-1. All patients successfully completed the procedure; none required additional sedation. P-deletion, reaction time, and critical flicker fusion tests revealed similar depression in both groups immediately postoperatively. After 30 min the p-deletion and critical flicker fusion scores were still impaired in the midazolam, but not in the propofol, group.
Topics: Analgesia, Patient-Controlled; Female; Humans; Hypnotics and Sedatives; Infusion Pumps; Midazolam; Oocytes; Patient Satisfaction; Propofol; Psychomotor Performance; Time Factors
PubMed: 8285322
DOI: 10.1111/j.1365-2044.1993.tb07521.x -
CJEM Mar 2022
Topics: Anesthetics, Dissociative; Haloperidol; Humans; Hypnotics and Sedatives; Ketamine; Midazolam
PubMed: 34971446
DOI: 10.1007/s43678-021-00249-x -
Systematic Reviews Dec 2022The sedative effect of intraoperative sedation in elderly surgery exerts critical influence on the prognosis. Comparison on the safety and efficacy between...
A comprehensive evaluation between dexmedetomidine and midazolam for intraoperative sedation in the elderly: protocol for a systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
The sedative effect of intraoperative sedation in elderly surgery exerts critical influence on the prognosis. Comparison on the safety and efficacy between dexmedetomidine and midazolam in many clinical randomized controlled trials (RCTs) was inconsistent and suspicious. We aim to comprehensively evaluate the safety and efficacy between dexmedetomidine and midazolam for intraoperative sedation in the elderly via meta-analysis and systematic reviews.
METHODS
RCTs regarding to the comparison of sedative effects and safety between dexmedetomidine and midazolam in elderly patients (aged ≥ 60 years) will be comprehensively searched from 2000 October to 2022 May through 4 English databases and 4 Chinese databases. After extraction in duplicate, the systematic review and meta-analysis will be performed on the primary outcomes (hemodynamic changes, sedative effect, cognitive function) and secondary outcomes (analgesic effect, surgical characteristics, complications, or adverse reactions) for assessing the two therapy methods using Review Manager software (Version 5.3). Sensitivity analysis will be conducted to evaluate the heterogeneity of the results; funnel plot and Egger's trial will be performed to analyze publication bias of the included studies, and trial sequential analysis will be applied to assess the robustness and reliability of preliminary meta-analysis results. Finally, rating quality of evidence and strength of recommendations on the meta results will be summarized by Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.
DISCUSSION
This systematic review and meta-analysis will evaluate the safety and efficacy between dexmedetomidine and midazolam for intraoperative sedation in the elderly; it will give an insight on the application of dexmedetomidine and midazolam and will provide evidence-based reference for clinical decision-making.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42021221897.
Topics: Humans; Aged; Midazolam; Dexmedetomidine; Randomized Controlled Trials as Topic; Systematic Reviews as Topic; Meta-Analysis as Topic; Hypnotics and Sedatives
PubMed: 36564829
DOI: 10.1186/s13643-022-02144-7 -
The pharmacokinetics and pharmacodynamics of midazolam after intravenous administration to donkeys .Canadian Journal of Veterinary Research... Apr 2022The pharmacokinetics and pharmacodynamics of midazolam were studied in eight 1-to-3-year-old healthy gelded donkeys. Blood samples were obtained. Heart rate, respiratory...
The pharmacokinetics and pharmacodynamics of midazolam were studied in eight 1-to-3-year-old healthy gelded donkeys. Blood samples were obtained. Heart rate, respiratory rate, rectal temperature, sedation/excitement, ataxia, and response to tactile and auditory stimuli were recorded at baseline until 48 hours after intravenous (IV) midazolam (0.1 mg/kg) administration. Plasma midazolam and 1-hydroxymidazolam were measured using reversed-phase high-performance liquid chromatography. Pharmacokinetic variables were calculated using non-compartmental analysis. Physiologic data were analyzed using a mixed-effects model followed by Dunnett's test and behavioral data were analyzed using a Friedman test then a Dunn's test; < 0.05 was considered significant. Midazolam was detectable for up to 60 minutes post-treatment in 7 donkeys. The median total body clearance, volume of distribution at steady state, elimination half-life, and area under concentration-time profile were 1210 mL/kg/h, 359 mL/kg, 0.27 hours, and 82.7 h × ng/mL, respectively. 1-hydroxymidazolam was detected (29 to 105 ng/mL) between 5 to 15 minutes post-treatment in 4 donkeys. Compared to baseline, rectal temperature and ataxia increased from 90 to 720 minutes ( ≤ 0.038) and 3 to 15 minutes ( ≤ 0.024) post-treatment, respectively. No other parameters showed statistically significant differences. Healthy donkeys cleared midazolam rapidly from plasma after IV administration. Transient ataxia and recumbency without sedation were observed.
Topics: Administration, Intravenous; Animals; Ataxia; Equidae; Half-Life; Midazolam
PubMed: 35388227
DOI: No ID Found -
Epilepsia Open Dec 2021Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABA R) and an increase in N-methyl-D-aspartate...
OBJECTIVE
Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABA R) and an increase in N-methyl-D-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) that may contribute to pharmacoresistance when treatment with benzodiazepine antiseizure medication is delayed. The barbiturate phenobarbital enhances inhibitory neurotransmission by binding to a specific site in the GABA R to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate-induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman-induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist.
METHODS
We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABA R modulator (midazolam and phenobarbital, respectively) to correct loss of inhibition, and ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDA-dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI-6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset.
RESULTS
The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman-induced epileptogenesis and reduced neurodegeneration. In addition, dual therapy with phenobarbital and midazolam or ketamine was more effective than monotherapy (midazolam or phenobarbital) in reducing cholinergic-induced toxicity.
SIGNIFICANCE
Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine-refractory cholinergic-induced SE, simultaneous drug combination to include drugs that target both the loss of inhibition (eg, midazolam, phenobarbital) and the increased excitatory response (eg, ketamine) is more effective than benzodiazepine or barbiturate monotherapy.
Topics: Animals; Anticonvulsants; Brain; Drug Therapy, Combination; Ketamine; Midazolam; Phenobarbital; Rats; Soman
PubMed: 34657398
DOI: 10.1002/epi4.12552 -
Anaesthesia Aug 1993
Topics: Abreaction; Aged; Anesthesia, Spinal; Humans; Male; Midazolam
PubMed: 8214481
DOI: 10.1111/j.1365-2044.1993.tb07215.x -
Neuropharmacology Dec 2022Genetic sequencing is identifying an expanding number of variants of GABA receptors associated with human epilepsies. We identified a new de novo variant of the β2...
Genetic sequencing is identifying an expanding number of variants of GABA receptors associated with human epilepsies. We identified a new de novo variant of the β2 subunit (β2L51M) of the inhibitory GABA receptor associated with seizures. Our analysis determined the pathogenicity of the variant and the effects of anti-seizure medications. Our data demonstrates that the variant reduced cell surface trafficking and peak GABA-gated currents. Synaptic currents mediated by variant-containing receptors decayed faster than wild-type and single receptor currents showed that the variant shortened the duration of receptor activity by decreasing receptor open times. We tested the effects of the anti-seizure medications, midazolam, carbamazepine and valproate and found that all three enhance variant receptor surface expression. Additionally, midazolam restored receptor function by increasing single receptor active periods and synaptic current decay times towards wild-type levels. By contrast, valproate increased synaptic peak currents, event frequency and promoted synaptic bursting. Our study identifies a new disease-causing variant to the GABA receptor, profiles its pathogenic effects and demonstrates how anti-seizure drugs correct its functional deficits.
Topics: Humans; Receptors, GABA-A; Valproic Acid; Midazolam; Epilepsy; gamma-Aminobutyric Acid
PubMed: 36257447
DOI: 10.1016/j.neuropharm.2022.109295 -
JPMA. the Journal of the Pakistan... Feb 2021To compare the efficacy of intravenous midazolam and diazepam in the management of status epilepticus seizures in children.
OBJECTIVE
To compare the efficacy of intravenous midazolam and diazepam in the management of status epilepticus seizures in children.
METHODS
The comparative study was conducted in the paediatric neurological emergency unit of The Children's Hospital and the Institute of Child Health, Multan, Pakistan, from December 15, 2018, to May 14, 2019, and comprised paediatric patients of status epilepticus seizures which were divided into Diazepam and Midazolam groups. Data was analysed using Graph-Pad Prism 5.
RESULTS
Of the 164 patients, 82(50%) were in each of the two groups. There was no significant difference between the groups in terms of weight, age, residence area of patients and mean duration of seizures (p>0.05). Status epilepticus seizures subsided after intravenous midazolam administration in 77(93.90%) cases, while success in the diazepam group 64(78.05%) (p<0.05). Mean time taken by midazolam to halt seizures was significantly shorter than diazepam (p<0.05) and less cases of treatment failure were observed with intravenous midazolam (p<0.05). Somnolence was observed after diazepam administration in 47(57.3%) cases (p=0.0001).
CONCLUSION
Intravenous midazolam was found to be superior in efficacy than intravenous diazepam in controlling status epilepticus seizures.
Topics: Anticonvulsants; Child; Diazepam; Humans; Midazolam; Pakistan; Status Epilepticus
PubMed: 33941951
DOI: 10.47391/JPMA.843 -
Drug Design, Development and Therapy 2020To compare the efficacy of dexmedetomidine and midazolam in the prevention of postoperative nausea and vomiting (PONV) caused by hemabate in postpartum hemorrhage during... (Comparative Study)
Comparative Study Randomized Controlled Trial
A Comparison of Dexmedetomidine and Midazolam for the Prevention of Postoperative Nausea and Vomiting Caused by Hemabate in Cesarean Delivery: A Randomized Controlled Trial.
OBJECTIVE
To compare the efficacy of dexmedetomidine and midazolam in the prevention of postoperative nausea and vomiting (PONV) caused by hemabate in postpartum hemorrhage during cesarean delivery.
METHODS
One hundred and five parturients with American Society of Anesthesiology (ASA) physical status I and II, aged 20-40 years, undergoing elective cesarean delivery under epidural anesthesia were randomly allocated into dexmedetomidine group (group D, n=35), midazolam group (group M, n=35) and control group (group C, n=35). Patients received an intrauterine injection of 250 μg hemabate and continuous intravenous infusion of 5 units oxytocin immediately following the delivery of the infant. At the same time, patients in group D received 1μg/kg intravenous dexmedetomidine, group M received 0.02 mg/kg intravenous midazolam and group C received 20 mL intravenous saline. Parameters such as the PONV, other adverse reactions (chest distress, flush, etc.) caused by hemabate, patient satisfaction, the sedation (OAA/S) scores, and the hemodynamic parameters were recorded in both groups.
RESULTS
The PONV incidence in group D and group M was significantly lower compared with group C (6%, 17%, and 71% for group D, group M, and group C, respectively, P<0.05). The sedation (OAA/S) scores in group D and group M was significantly higher compared with group C (1.62±0.28, 1.75±0.31, and 1.00±0.00 for group D, group M, and group C, respectively, P<0.05). The patient satisfaction in group D and group M was significantly higher compared with group C (94%, 69%, and 46% for group D, group M, and group C, respectively, P<0.05). Furthermore, there were more patients satisfied with group D than group M (94% vs.69%, P<0.05).
CONCLUSION
Intravenous dexmedetomidine (1 μg/kg) and midazolam (0.02 mg/kg) were equally effective in preventing PONV introduced by hemabate and dexmedetomidine is superior to midazolam in patient satisfaction.
Topics: Adult; Cesarean Section; Dexmedetomidine; Female; Humans; Injections, Intravenous; Midazolam; Postoperative Nausea and Vomiting; Postpartum Hemorrhage; Pregnancy; Young Adult
PubMed: 32546975
DOI: 10.2147/DDDT.S251525