Comparison of propofol-based sedation and midazolam sedation in pediatric bidirectional endoscopy conducted by pediatric gastroenterologists.

Objectives: The effectiveness and safety of propofol-based sedation and midazolam sedation in pediatric bidirectional endoscopy were compared. Methods: We retrospectively analyzed the cases of pediatric patients (≤15 years old) who had undergone bidirectional endoscopy, esophagogastroduodenoscopy, and colonoscopy by pediatric gastroenterologists. Demographic data, indications, sedatives/dosages, clinical outcomes, endoscopic findings, adverse events, and total patient time requirements (total time in which patients stay in our hospital) were compared in the two sedation groups. Results: Ninety-one children (51 boys, 40 girls, mean age 13 years, range 9-15) treated at our hospital were enrolled. Propofol alone or in combination with midazolam and/or pentazocine was administered to 51 patients (propofol-based sedation group). Midazolam alone or in combination with pentazocine was administered to the other 40 patients (midazolam sedation group). In the propofol group, the following mean doses were used: propofol, 96 mg (range 40-145 mg); midazolam, 4.9 mg (range 3-5 mg); and pentazocine, 7.5 mg. In the midazolam group, the mean doses of midazolam and pentazocine were 6.2 mg (range 4-10 mg) and 15 mg, respectively. All procedures were successfully completed by pediatric gastroenterologists. The total procedure times and endoscopic findings were similar in the two groups, but the median patient time requirement in the propofol group was significantly shorter versus the midazolam group (7.3 h vs. 8.4 h, p < 0.001). No adverse events occurred in either group. Conclusions: Propofol-based sedation in pediatric bidirectional endoscopy was safely and effectively performed by pediatric gastroenterologists, and its patient time requirement was shorter than that for midazolam sedation.

Perioperative use of immersive head-mounted virtual reality display enhances patient satisfaction in great saphenous vein surgery: a single-center clinical observation study.

OBJECTIVE: To explore the application effect of head-mounted virtual reality display immersive experience in improving the perioperative satisfaction of patients undergoing great saphenous vein surgery. METHODS: A total of 158 patients undergoing saphenous vein surgery at the First Affiliated Hospital, Jiangxi Medical College, Nanchang University from January 2020 to January 2023 were randomly divided into an observation group and a control group in a 1:1 ratio, with 79 cases in each group. The observation group received head-mounted display virtual reality immersive experience, whereas the control group received midazolam. The study compared the perioperative satisfaction, changes in preoperative and postoperative anxiety and depression scores, intraoperative blood pressure and heart rate, postoperative visual analog scale (VAS) score, and the incidence of postoperative nausea and vomiting between the two groups. Additionally, the satisfaction of patients, anesthesiologists, and chief surgeons was compared. RESULTS: All surgeries were completed successfully. Patients in the observation group exhibited higher perioperative satisfaction compared to those in the control group (P<0.001). There were no significant differences in anxiety or depression scores between the two groups before surgery (P>0.05). However, both groups showed a reduction in anxiety and depression scores postoperatively, with the observation group demonstrating lower scores than the control group (both P<0.05). The observation group also had lower intraoperative blood pressure, heart rate, postoperative VAS scores, and incidence of nausea and vomiting compared to the control group (all P<0.05). Furthermore, the satisfaction levels of the anesthesiologists and chief surgeons were higher in the observation group than in the control group (P=0.043, 0.012). CONCLUSION: Head-mounted display virtual reality immersive experience can enhance perioperative satisfaction among patients undergoing great saphenous vein surgery, reduce anxiety and depression scores, and contribute to the stabilization of hemodynamics during surgery, thereby decreasing postoperative nausea and vomiting.

An analysis of oxidative stress indices and clinical parameters in budgerigars (Melopsittacus undulatus) treated with medetomidine-ketamine and midazolam-ketamine.

Various companion birds, including budgerigars, are anesthetized with injectable anesthesia. The current study aimed to evaluate oxidative stress indices including malondialdehyde (MDA), total antioxidant capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI) along with clinical parameters such as the time required to induce, maintain and recover from medetomidine-ketamine anesthesia and midazolam-ketamine anesthesia in budgerigars. Among 20 mature and healthy budgerigars, three groups were assigned as follows: Control (n = 4) to determine baseline oxidative stress indices medetomidine + ketamine (n = 8) anesthetized by intramuscular injections of medetomidine (0.04 mg kg-1) and ketamine (30.00 mg kg-1) in the pectoral muscles, midazolam + ketamine (n = 8) anesthetized by intramuscular injections of midazolam (1.00 mg kg-1) and ketamine (50.00 mg kg-1). Half of birds (n = 4) in the second and third groups were euthanized by cervical dislocation 1 hr after anesthesia induction, blood samples were collected directly from the heart, and sera were extracted. Additionally, the remaining birds were euthanized 24 hr later, and their serum was analyzed for oxidative stress indices. Clinical parameters were recorded during the study. Compared to the medetomidine + ketamine group, the midazolam + ketamine group experienced shorter induction, anesthetic, and recovery times. Administering medetomidine and ketamine elevated TOS levels compared with midazolam + ketamine. No significant difference was found between the test groups for TAC, MDA, or OSI. Therefore, the midazolam + ketamine regimen appears superior to medetomidine + ketamine when performing minor surgeries on budgerigars.

Challenges of status epilepticus management in a resource-limited setting: A review.

Status epilepticus (SE) is a life-threatening neurological condition with significant mortality. Rapid management is essential to minimize the mortality and disability of SE. Two recent trials provided evidence to guide SE management in early and established stages. The Rapid Anticonvulsant Medication Prior To Arrival Trial (RAMPART, 2011) showed that intramuscular midazolam is a better alternative for early convulsive SE in prehospital settings. The Established Status Epilepticus Treatment Trial (ESETT, 2020) supported the use of sodium valproate and levetiracetam as second-line treatment for its efficacy and shorter administration time. However, there are challenges to revising the status epilepticus management in resource-limited settings, in pre-hospital, first- and second-line treatment, as well as management of refractory and super-refractory SE. These challenges included restrictions or lack of training in the administration of benzodiazepine in the prehospital setting, limited availability and accessibility of newer antiseizure medications (ASMs) in emergency departments and smaller hospitals, and low clinicians' awareness of the latest evidence. A collaborative effort to educate, improve awareness, and make certain ASMs more readily available is recommended to achieve a better clinical outcome in SE.

Stability of Multicomponent Antidote Parenteral Formulations for Autoinjectors against Chemical War Agents (Neurotoxics).

Combinations of different drugs are formulated in autoinjectors for parenteral administration against neurotoxic war agents. In this work, the effects on the chemical stability of the following three variables were studied: (i) type of drug combination (pralidoxime, atropine, and midazolam versus obidoxime, atropine, and midazolam); (ii) pH (3 versus 4); and (iii) type of elastomeric sealing material (PH 701/50 C BLACK versus 4023/50 GRAY). Syringes were stored at three different temperatures: 4, 25, and 40 °C. Samples were assayed at different time points to study the physical appearance, drug sorption on the sealing elastomeric materials, and drug content in solution. Midazolam was unstable in all tested experimental conditions. Drug adsorption was observed in both types of sealing elastomeric materials and was significantly (p < 0.01) dependent on the lipophilicity of the drug. The most stable formulation was the combination of pralidoxime and atropine at pH 4 with the elastomeric sealing material 4023/50 GRAY.

An evaluation of dexmedetomidine in combination with midazolam in pediatric sedation: a systematic review and 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, I2 = 51%; OR = 0.23, 95% CI: 0.07-0.68, P = 0.008, I2 = 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, I2 = 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, I2 = 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.

Early Postnatal Exposure to Midazolam Causes Lasting Histological and Neurobehavioral Deficits via Activation of the mTOR Pathway.

Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar pharmacologic mechanisms. Using quantitative immunohistochemistry and neurobehavioral testing and an established protocol for murine sedation, we tested the hypothesis that lengthy, repetitive exposure to midazolam, a commonly used sedative in pediatric intensive care, interferes with neuronal development and subsequent cognitive function via actions on the mechanistic target of rapamycin (mTOR) pathway. We found that mice in the midazolam sedation group exhibited a chronic, significant increase in the expression of mTOR activity pathway markers in comparison to controls. Furthermore, both neurobehavioral outcomes, deficits in Y-maze and fear-conditioning performance, and neuropathologic effects of midazolam sedation exposure, including disrupted dendritic arborization and synaptogenesis, were ameliorated via treatment with rapamycin, a pharmacologic mTOR pathway inhibitor. We conclude that prolonged, repetitive exposure to midazolam sedation interferes with the development of neural circuitry via a pathologic increase in mTOR pathway signaling during brain development that has lasting consequences for both brain structure and function.

Effects of ketamine on the severity of depression and anxiety following postoperative mechanical ventilation: a single-blind randomized clinical trial in Iran.

BACKGROUND: In this study, we compare the effects of ketamine and the combination of midazolam and morphine on the severity of depression and anxiety in mechanically ventilated patients after discharge from the intensive care unit (ICU). METHODS: This randomized single-blind clinical trial included 50 patients who were candidates for craniotomy and postoperative mechanical ventilation in the ICU of 5 Azar Teaching Hospital in Gorgan City, North Iran, from 2021 to 2022. Patients were allocated to two groups by quadruple block randomization. In group A, 0.5 mg/kg of ketamine was infused over 15 minutes after craniotomy and then continued at a dose of 5 µ/kg/min during mechanical ventilation. In group B, midazolam was infused at a dose of 2-3 mg/hr and morphine at a dose of 3-5 mg/hr. After patients were discharged from the ICU, if their Glasgow Coma Scale scores were ≥14, Beck's anxiety and depression inventories were completed by a psychologist within 2 weeks, 2 months, and 6 months after discharge. RESULTS: The mean scores of depression at 2 months (P=0.01) and 6 months (P=0.03) after discharge were significantly lower in the ketamine group than in the midazolam and morphine group. The mean anxiety scores were significantly lower in the ketamine group 2 weeks (P=0.006) and 6 months (P=0.002) after discharge. CONCLUSIONS: Ketamine is an effective drug for preventing and treating anxiety and depression over the long term in patients discharged from the ICU. However, further larger volume studies are required to validate these results.

Optimizing anesthesia strategies to NSCLC patients in VATS procedures: Insights from drug requirements and patient recovery patterns.

Understanding the intricate relationship between cancer clinicopathological features and anesthetics dosage is crucial for optimizing patient outcomes and safety during surgery. This retrospective study investigates this relationship in patients with non-small cell lung cancer (NSCLC) undergoing video-assisted thoracic surgery (VATS). A comprehensive analysis of medical records was undertaken for NSCLC patients who underwent VATS with intravenous compound inhalation general anesthesia. Patients were categorized based on histological, chemotherapy, radiotherapy, and epidural anesthesia factors. Statistical analysis was performed to compare the differences between the groups. The results revealed compelling insights. Specifically, patients with lung adenocarcinoma (LUAD) undergoing VATS exhibited higher dosages of rocuronium bromide and midazolam during general anesthesia, coupled with a shorter post-anesthesia care unit (PACU) stay compared to those with squamous cell carcinoma (sqCL). Furthermore, chemotherapy patients undergoing VATS demonstrated diminished requirements for phenylephrine and remifentanil in contrast to their non-chemotherapy counterparts. Similarly, radiotherapy patients undergoing VATS demonstrated a decreased necessity for rocuronium bromide compared to non-radiotherapy patients. Notably, patients who received epidural anesthesia in combination with general anesthesia manifested reduced hydromorphone requirements and prolonged hospital stays compared to those subjected to general anesthesia alone. In conclusion, the findings from this study indicate several important observations in diverse patient groups undergoing VATS. The higher dosages of rocuronium bromide and midazolam in LUAD patients point to potential differences in drug requirements among varying lung cancer types. Additionally, the observed shorter PACU stay in LUAD patients suggests a potentially expedited recovery process. The reduced anesthetic requirements of phenylephrine and remifentanilin chemotherapy patients indicate distinct responses to anesthesia and pain management. Radiotherapy patients requiring lower doses of rocuronium bromide imply a potential impact of prior radiotherapy on muscle relaxation. Finally, the combination of epidural anesthesia with general anesthesia resulted in reduced hydromorphone requirements and longer hospital stays, suggesting the potential benefits of this combined approach in terms of pain management and postoperative recovery. These findings highlight the importance of tailoring anesthesia strategies for specific patient populations to optimize outcomes in VATS procedures.

Total intravenous anesthesia with Ketofol in rabbits: a comparison of the effects of constant rate infusion of midazolam, fentanyl or dexmedetomidine.

BACKGROUND: When inhalant anesthetic equipment is not available or during upper airway surgery, intravenous infusion of one or more drugs are commonly used to induce and/or maintain general anesthesia. Total intravenous anesthesia (TIVA) does not require endotracheal intubation, which may be more difficult to achieve in rabbits. A range of different injectable drug combinations have been used as continuous infusion rate in animals. Recently, a combination of ketamine and propofol (ketofol) has been used for TIVA in both human patients and animals. The purpose of this prospective, blinded, randomized, crossover study was to evaluate anesthetic and cardiopulmonary effects of ketofol total intravenous anesthesia (TIVA) in combination with constant rate infusion (CRI) of midazolam, fentanyl or dexmedetomidine in eight New Zealand White rabbits. Following IV induction with ketofol and endotracheal intubation, anesthesia was maintained with ketofol infusion in combination with CRIs of midazolam (loading dose [LD]: 0.3 mg/kg; CRI: 0.3 mg/kg/hr; KPM), fentanyl (LD: 6 µg/kg; CRI: 6 µg/kg/hr; KPF) or dexmedetomidine (LD: 3 µg/kg; CRI: 3 µg/kg/hr; KPD). Rabbits in the control treatment (KPS) were administered the same volume of saline for LD and CRI. Ketofol infusion rate (initially 0.6 mg kg- 1 minute- 1 [0.3 mg kg- 1 minute- 1 of each drug]) was adjusted to suppress the pedal withdrawal reflex. Ketofol dose and physiologic variables were recorded every 5 min. RESULTS: Ketofol induction doses were 14.9 ± 1.8 (KPM), 15.0 ± 1.9 (KPF), 15.5 ± 2.4 (KPD) and 14.7 ± 3.4 (KPS) mg kg- 1 and did not differ among treatments (p > 0.05). Ketofol infusion rate decreased significantly in rabbits in treatments KPM and KPD as compared with saline. Ketofol maintenance dose in rabbits in treatments KPM (1.0 ± 0.1 mg/kg/min) and KPD (1.0 ± 0.1 mg/kg/min) was significantly lower as compared to KPS (1.3 ± 0.1 mg/kg/min) treatment (p < 0.05). Ketofol maintenance dose did not differ significantly between treatments KPF (1.1 ± 0.3 mg/kg/min) and KPS (1.3 ± 0.1 mg/kg/min). Cardiovascular variables remained at clinically acceptable values but ketofol infusion in combination with fentanyl CRI was associated with severe respiratory depression. CONCLUSIONS: At the studied doses, CRIs of midazolam and dexmedetomidine, but not fentanyl, produced ketofol-sparing effect in rabbits. Mechanical ventilation should be considered during ketofol anesthesia, particularly when fentanyl CRI is used.

Optimising the oral midazolam dose for premedication in people with intellectual disabilities and/or autism spectrum disorder.

BACKGROUND: In people with intellectual disabilities and/or autism spectrum disorder, oral midazolam (OM) is very effective as premedication for facilitating medical treatment. In this retrospective study, we investigated the optimal dosage of OM for premedication. METHODS: Patients with intellectual disability and/or autism spectrum disorder who were given OM as a premedication were selected from anaesthesia records. The primary outcome variable was the dose of OM (mg/kg) required to produce an adequate sedation. RESULTS: The mean OM dose required was 0.32 ± 0.10 mg/kg. The required OM dose decreased significantly as age and weight increased, and age and weight were also shown to be significantly associated with the dose of OM in the multivariate linear regression analysis. CONCLUSION: The dosage of OM to achieve adequate sedation should decrease as the patient ages. Furthermore, adequate sedation can be achieved with even lower doses of OM in obese people.

[Oral sedation in pediatric outpatient dentistry]. / Primenenie peroral'noi sedatsii pri ambulatornom stomatologicheskom vmeshatel'stve u detei.

THE AIM OF THE STUDY: Was to improve the quality of treatment in pediatric outpatient dentistry with the effective use of oral sedation. MATERIALS AND METHODS: The study comprised 60 children aged 3-12 years who were undergoing therapeutic/surgical dental treatment. All children's somatic state was assessed as ASAI-II. All children met a number of psychological, anamnestic and procedural criteria. Midazolam and chloropyramine in a dose calculated for the patient's body weight were used as components of oral sedation. The estimated sedation depth was Ramsay II-III. The study included an analysis of objective (the time of comfortable treatment, the amount of treated or removed teeth per visit, the possibility of treatment without anesthesia during further visits) and subjective (the possibility of contact with the child during treatment, behavioral reactions at home and on further visits) criteria. Negative behavioral reactions and dental effects were also assessed. RESULTS: The treatment features correlated with the age category and gender of the patient. In the older age group of 7-12 years, the amount of comfortable treatment time was higher, the possibility of contact with the child reached 100% (which is twice as much as in the younger one), and also a larger number of patients were treated during further visits without an anesthetic aid. At the same time, in the younger age group of 3-6 years, the volume of treatment per visit was higher, since it takes less time to treat a primary tooth than for a permanent one. Side effects (visual hallucinations, diplopia, hyperactivity, tearfulness and aggressiveness) were more often recorded in the younger age group, but emotional instability was equally manifested in both groups. CONCLUSION: In order to maximize the effectiveness of using oral sedation as a method, it is necessary to take into account the duration and traumatism of the proposed procedure, the peculiarities of age psychology and the peculiarities of the psychological development of boys and girls.

Anesthetic Challenges during Endobronchial Brachytherapy: A Case Report.

Lung cancer is the leading cause of cancer death worldwide. It may present as airway obstruction in a patient with endobronchial masses. Endobronchial brachytherapy (EBBT) has been shown to provide palliative therapy. It is the insertion of a radioactive material near the mass to reduce tumor size, thereby improving airway obstruction. This is the first case of EBBT done in our institution during the COVID-19 pandemic. A 53-year-old male, 60 kg, ASA Physical Status 2 for hypertension, smoker, malignancy, and previous pulmonary tuberculosis patient, presented with a cough and dyspnea. An endobronchial mass almost obstructing the right mainstem bronchus was seen on a computed tomography (CT) scan. He was diagnosed with squamous cell carcinoma of the lung and underwent radiotherapy and erlotinib chemotherapy. On repeat CT scan, there was no noted decrease in the size of the mass. EBBT was suggested, and a multi-disciplinary team was formed for the planned procedure. Pulmonology, radiation oncology, and anesthesiology teams were identified, and thorough planning was done prior to the actual procedure. Three fractions of EBBT were done under sedation using midazolam, fentanyl, and dexmedetomidine infusion. Lidocaine spray and transtracheal block were also performed as adjuncts prior to sedation. The procedure went as planned, and points for improvement were discussed for subsequent fractions. Due to persistent cough and discomfort from the catheter, additional ipratropium nebulization for minimization of secretions, and oral dextromethorphan for cough suppression were incorporated. After each fraction, the patient was monitored post-procedure for any side effects both from the radiotherapy and anesthetic technique. Qualitative reduction in mass size was noted in subsequent fractions. The patient was able to complete 3 fractions and was advised to follow-up after a month. EBBT is an emerging palliative and treatment modality for lung cancer, especially for intraluminal masses. Anesthetic considerations will depend on each case's characteristics such as airway anatomy, patient comfort and capacity, and procedural requirements. Conscious sedation with topical anesthesia is an adequate and appropriate anesthetic option, especially in cases where severe airway obstruction may compromise ventilation if airway reflexes are blunted. A multidisciplinary approach with different services and stakeholders is important for the proper planning, execution, and management of such patients.

Evaluating the effectiveness of the maximum permitted dose of midazolam in seizure termination: Insights from New South Wales, Australia.

OBJECTIVE: Out-of-hospital seizures demand rapid management. Midazolam plays a key role in stopping seizures. At times the first dose of midazolam proves insufficient, necessitating additional doses. Within the New South Wales Ambulance (NSWA) service, the upper limit for midazolam administration is set at 15 mg. However, the outcomes and safety of using midazolam at this maximum dosage have not been thoroughly investigated. METHODS: A retrospective analysis of out of hospital electronic health records from New South Wales, Australia, over the year 2022, was conducted. The study manually reviewed cases where adult patients received the maximum dose of midazolam for seizure management by paramedics. It focused on seizure cessation success rates and the incidence of adverse effects to evaluate the clinical implications of high-dose midazolam administration. RESULTS: Of 818 790 individual attendances by NSWA clinicians, a total of 11 392 (1.4%) adults had seizures noted, of which midazolam was administered in 2565 (22.5%). An algorithm shows that in 2352 (91.7%) instances the midazolam was associated with the apparent termination of seizures. Analysis revealed that 176 (1.5%) proportion of all adult's seizure patients required the maximum dose of midazolam for seizure control. These higher doses successfully terminate seizures in about half of the instances. AEs following the maximum dose of midazolam included hypoxia in 26.7% of patients and respiratory depression in 9.7%, indicating significant side effects at higher dosages. CONCLUSION: In New South Wales, Australia, administering the maximum dose of midazolam to seizure patients is rare but proves effective in approximately half of the refractory seizure cases. Therefore, assessing the potential for additional doses of midazolam or the use of a second-line agent is advisable.

A drug-drug interaction study and physiologically based pharmacokinetic modelling to assess the effect of an oral 5-lipoxygenase activating protein inhibitor on the pharmacokinetics of oral midazolam.

AIMS: Early clinical studies have indicated that the pharmacokinetics of Atuliflapon (AZD5718) are time and dose dependent. The reason(s) for these findings is(are) not fully understood, but pre-clinical profiling suggests that time-dependent CYP3A4 inhibition cannot be excluded. In clinical practice, Atuliflapon will be co-administered with CYP3A4 substrates; thus, it is important to determine the impact of Atuliflapon on the pharmacokinetics (PK) of CYP3A4 substrates. The aim of this study was to evaluate the effect of Atuliflapon on the pharmacokinetics of a sensitive CYP3A4 substrate, midazolam, and to explore if the time-/dose-dependent effect seen after repeated dosing could be an effect of change in CYP3A4 activity. METHODS: Open-label, fixed-sequence study in healthy volunteers to assess the PK of midazolam alone and in combination with Atuliflapon. Fourteen healthy male subjects received single oral dose of midazolam 2 mg on days 1 and 7 and single oral doses of Atuliflapon (125 mg) from days 2 to 7. A physiologically based pharmacokinetic (PBPK) model was developed to assess this drug-drug interaction. RESULTS: Mean midazolam values of maximum plasma concentration (Cmax) and area under the curve (AUC) to infinity were increased by 39% and 56%, respectively, when co-administered with Atuliflapon vs. midazolam alone. The PBPK model predicted a 27% and 44% increase in AUC and a 23% and 35% increase in Cmax of midazolam following its co-administrations with two predicted therapeutically relevant doses of Atuliflapon. CONCLUSIONS: Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs.

Comparison of intranasal dexmedetomidine versus oral midazolam for premedication in pediatric patients: an updated meta-analysis with trial-sequential analysis.

BACKGROUND: Midazolam is routinely used as preanesthetic medication in pediatric patients. Recently, dexmedetomidine has emerged as an alternative as a premedicant. We aimed to add more evidence about the efficacy and safety of two common routes of administration for pediatric premedication: oral midazolam versus intranasal dexmedetomidine. METHODS: We systematically searched Randomized Controlled Trials (RCTs) involving patients ≤ 18 years old undergoing preanesthetic medication and comparing intranasal dexmedetomidine with oral midazolam. Risk Ratio (RR) and Mean Difference (MD) with 95% Confidence Intervals (95% CI) were computed using a random effects model. Trial-sequential analyses were performed to assess inconsistency. RESULTS: Sixteen RCTs (1,239 patients) were included. Mean age was 5.5 years old, and most procedures were elective. There was no difference in satisfactory induction or mask acceptance (RR = 1.15, 95% CI 0.97-1.37; p = 0.11). There was a higher incidence of satisfactory separation from parents in the dexmedetomidine group (RR = 1.40; 95% CI 1.13-1.74; p = 0.002). Dexmedetomidine was also associated with a reduction in the incidence of emergence agitation (RR = 0.35; 95% CI 0.14-0.88; p = 0.02). Heart rate and mean arterial pressure were marginally lower in the dexmedetomidine group but without clinical repercussions. CONCLUSION: Compared with oral midazolam, intranasal dexmedetomidine demonstrated better separation from parents and lower incidence of emergence agitation in pediatric premedication, without a difference in satisfactory induction. Intranasal dexmedetomidine may be a safe and effective alternative to oral midazolam for premedication in pediatric patients.

Efficacy and cost analysis of intravenous conscious sedation for long oral surgery procedures.

The aim of this study was to determine what is considered a long oral surgery and conduct a cost-effective analysis of sedative agents used for intravenous sedation (IVS) and sedation protocols for such procedures. Pubmed and Google Scholar databases were used to identify human studies employing IVS for extractions and implant-related surgeries, between 2003 and July/2023. Sedation protocols and procedure lengths were documented. Sedative satisfaction, operator satisfaction, and sedation assessment were also recorded. Cost estimation was based on The British National Formulary (BNF). To assess bias, the Cochrane Risk of Bias tools were employed. This review identified 29 randomised control trials (RCT), six cohorts, 14 case-series, and one case-control study. The study defined long procedures with an average duration of 31.33 minutes for extractions and 79.37 minutes for implant-related surgeries. Sedative agents identified were midazolam, dexmedetomidine, propofol, and remimazolam. Cost analysis revealed midazolam as the most cost-effective option (<10 pence per procedure per patient) and propofol the most expensive option (approximately £46.39). Bias analysis indicated varying degrees of bias in the included studies. Due to diverse outcome reporting, a comparative network approach was employed and revealed benefits of using dexmedetomidine, propofol, and remimazolam over midazolam. Midazolam, dexmedetomidine, propofol, and remimazolam demonstrated safety and efficacy as sedative agents for conscious IVS in extended procedures like extractions or implant-related surgeries. While midazolam is the most cost-effective option, dexmedetomidine, propofol, and remimazolam offer subjective and clinical benefits. The relatively higher cost of propofol may impede its widespread use. Dexmedetomidine and remimazolam stand out as closely priced options, necessitating further clinical investigations for comparative efficacy assessment.

No harmful effect of propranolol administered prior to fear memory extinction in rats and humans.

Exposure therapy is an evidence-based treatment option for anxiety-related disorders. Many patients also take medication that could, in principle, affect exposure therapy efficacy. Clinical and laboratory evidence indeed suggests that benzodiazepines may have detrimental effects. Large clinical trials with propranolol, a common beta-blocker, are currently lacking, but several preclinical studies do indicate impaired establishment of safety memories. Here, we investigated the effects of propranolol given prior to extinction training in 9 rat studies (N = 215) and one human study (N = 72). A Bayesian meta-analysis of our rat studies provided strong evidence against propranolol-induced extinction memory impairment during a drug-free test, and the human study found no significant difference with placebo. Two of the rat studies actually suggested a small beneficial effect of propranolol. Lastly, two rat studies with a benzodiazepine (midazolam) group provided some evidence for a harmful effect on extinction memory, i.e., impaired extinction retention. In conclusion, our midazolam findings are in line with prior literature (i.e., an extinction retention impairment), but this is not the case for the 10 studies with propranolol. Our data thus support caution regarding the use of benzodiazepines during exposure therapy, but argue against a harmful effect of propranolol on extinction learning.

Clinical Evaluation of Oral Midazolam Containing Cyclodextrin in Pediatric Magnetic Resonance: A Retrospective Cohort Study.

BACKGROUND: Reducing a child's level of anxiety before magnetic resonance imaging (MRI) procedures allows for better behavioral outcomes. The aim of this retrospective study was to evaluate anxiolytic efficacy of Midazolam/γ-cyclodextrin oral formulation. METHODS: We retrospectively reviewed 100 medical charts of children who, between 1 February and 31 July 2022, underwent MRI under general anesthesia with or without premedication with midazolam/γ-cyclodextrin. Primary outcome was comparison of behavior to facemask positioning, while secondary endpoints were degree of drugs acceptance, anxiolytic effect evaluation, child's behavior on separation, and sevoflurane need. RESULTS: Facemask positioning was accepted by 58% of the midazolam/γ-cyclodextrin group compared to 22% of children in the control group. The rate of acceptance was >90%. At the moment of separation from parent, none of the premedicated children needed to be restrained compared to 18% in the control group. A lower percentage of sevoflurane was needed for eye-closure at induction of anesthesia and for anesthesia maintenance. At emergence from anesthesia, 46% of children in the premedicated group compared to 66% of children in the control group showed transient agitation. CONCLUSIONS: Midazolam/γ-cyclodextrin showed a good profile of acceptance, satisfactory anxiolytic properties, and reduced need for anesthetics when administered to children before MRI under general anesthesia.

Value of Assessing 1-Hydroxymidazolam in Drug-Drug Interaction Studies with Midazolam as a Substrate of Cytochrome P450 3A.

The purpose of this overview was to perform an exploratory analysis of in-house drug-drug interaction (DDI) studies conducted with investigational drugs and oral midazolam to assess the value of measuring 1-OH-midazolam (1-OHM) in such studies. The perpetrator effect of the investigational drugs on cytochrome P450 3A (CYP3A) was assessed by analyzing both midazolam and 1-OHM in plasma and evaluating their pharmacokinetic parameters. Given the almost exclusive metabolism of the parent drug by CYP3A to the main metabolite 1-OHM, an increase in midazolam and a decrease in 1-OHM exposure in the case of CYP3A inhibition caused by a perpetrator drug would be expected. The opposite would be anticipated in the case of CYP3A induction. For this analysis, the perpetrator potential of eight different investigational drugs was incorporated. Among the 10 studies included, the identified CYP3A inhibitors (n = 4) and inducers (n = 1) were classified based on the data generated with midazolam per se, with 1-OHM levels not contributing to the interpretation of the data as they did not corroborate the findings of the parent compound. Therefore, it was concluded that continued analysis of 1-OHM in plasma may be questionable as it does not add value to the interpretation of the results when performing CYP3A DDI studies with an investigational drug as a perpetrator.