Midazolam Increases The Risk of Delirium In Critically Ill Patients: A Propensity Score Analysis.

BACKGROUND: Midazolam is commonly administered in the intensive care unit (ICU) because of its limited effect on hemodynamics and stable calming and sleep-induction effects. Recent concerns about an increased risk of delirium associated with midazolam have resulted in decreased midazolam usage in the ICU. However, whether midazolam administration within 24 hours prior is related to the occurrence of delirium is still unknown.METHODS: We used real-world data from MIMIC III v1.4, MIMIC-IV v0.4 and eICU Collaborative Research to perform comparisons and assess the associated outcome effectiveness. We performed a systematic study with two cohorts to estimate the relative risks of outcomes among patients administered midazolam within 24 hours prior to delirium assessment. Propensity score matching was performed to generate a balanced 1:1 matched cohort and to identify potential prognostic factors. The outcomes included mortality, length of ICU stay, length of hospitalization, and odds of being discharged home.RESULTS: Propensity matching successfully balanced covariates for 9,348 patients (4,674 per group). There was no significant difference in hospitalization duration, (P = 0.03). However, compared to no administration of midazolam, midazolam administration was associated with a significantly higher risk for delirium (P<0.001). When compared with no midazolam administration, the use of midazolam, was associated with higher mortality and a longer ICU stay (P<0.001). Patients treated with midazolam were relatively less likely to be discharged home (P<0.001). CONCLUSIONS: Compared with no administration of midazolam, midazolam administration was associated with a difference in the incidence of delirium, mortality, ICU stay and likelihood of being discharged home but was not associated with hospitalization duration. These data suggest that midazolam may not be the preferred sedative drug for patients at risk for delirium.

Co Loading Adjustment for the Effective Obtention of a Sedative Drug Precursor through Efficient Continuous-Flow Chemoselective Hydrogenation of 2-Methyl-2-pentenal

This work presents the effect of Co loading on the performance of CNR115 carbon-supported catalysts in the continuous-flow chemoselective hydrogenation of 2-methyl-2-pentenal for the obtention of 2-methylpentanal, an intermediate in the synthesis of the sedative drug meprobamate. The Co loading catalysts (2, 6, 10, and 14 wt.%) were characterized by Brunauer–Emmett–Teller (BET) surface area analysis, transmission electron microscopy (TEM), H2 temperature-programmed reduction (H2-TPR), temperature-programmed desorption of hydrogen (H2-TPD) analysis, X-ray diffraction (XRD), and X-ray photoelectron spectroscopy for selected samples, and have been studied as hydrogenation catalysts at different pressure and temperature ranges. The results reveal that a certain amount of Co is necessary to achieve significant conversion values. However, excessive loading affects the morphological parameters, such as the surface area available for hydrogen adsorption and the particle size, preventing an increase in conversion, despite the increased presence of Co. Moreover, the larger particle size, caused by increasing the loading, alters the chemoselectivity, favouring the formation of 2-methyl-2-pentenol and, thus, decreasing the selectivity towards the desired product. The 6 wt.% Co-loaded material demonstrates the best catalytic performance, which is related to the formation of NPs with optimum size. Almost 100% selectivity towards 2-methylpentanal was obtained for the catalysts with lower Co loading (2 and 6 wt.%).

Associations Between High Plasma Methylxanthine Levels, Sleep Disorders and Polygenic Risk Scores of Caffeine Consumption or Sleep Duration in a Swiss Psychiatric Cohort

Objective: We first sought to examine the relationship between plasma levels of methylxanthines (caffeine and its metabolites) and sleep disorders, and secondarily between polygenic risk scores (PRS) of caffeine consumption or sleep duration with methylxanthine plasma levels and/or sleep disorders in a psychiatric cohort.Methods: Plasma levels of methylxanthines were quantified by ultra-high performance liquid chromatography/tandem mass spectrometry. In inpatients, sleep disorder diagnosis was defined using ICD-10 “F51.0,” sedative drug intake before bedtime, or hospital discharge letters, while a subgroup of sedative drugs was used for outpatients. The PRS of coffee consumption and sleep duration were constructed using publicly available GWAS results from the UKBiobank.Results: 1,747 observations (1,060 patients) were included (50.3% of observations with sleep disorders). Multivariate analyses adjusted for age, sex, body mass index, setting of care and psychiatric diagnoses showed that patients in the highest decile of plasma levels of methylxanthines had more than double the risk for sleep disorders compared to the lowest decile (OR = 2.13, p = 0.004). PRS of caffeine consumption was associated with plasma levels of caffeine, paraxanthine, theophylline and with their sum (β = 0.1; 0.11; 0.09; and 0.1, pcorrected = 0.01; 0.02; 0.02; and 0.01, respectively) but not with sleep disorders. A trend was found between the PRS of sleep duration and paraxanthine levels (β = 0.13, pcorrected = 0.09).Discussion: Very high caffeine consumption is associated with sleep disorders in psychiatric in- and outpatients. Future prospective studies should aim to determine the benefit of reducing caffeine consumption in high caffeine-consuming patients suffering from sleep disorders.

Anticancer Effects of Midazolam on Lung and Breast Cancers by Inhibiting Cell Proliferation and Epithelial-Mesenchymal Transition

Despite improvements in cancer treatments resulting in higher survival rates, the proliferation and metastasis of tumors still raise new questions in cancer therapy. Therefore, new drugs and strategies are still needed. Midazolam (MDZ) is a common sedative drug acting through the γ-aminobutyric acid receptor in the central nervous system and also binds to the peripheral benzodiazepine receptor (PBR) in peripheral tissues. Previous studies have shown that MDZ inhibits cancer cell proliferation but increases cancer cell apoptosis through different mechanisms. In this study, we investigated the possible anticancer mechanisms of MDZ on different cancer cell types. MDZ inhibited transforming growth factor β (TGF-β)-induced cancer cell proliferation of both A549 and MCF-7 cells. MDZ also inhibited TGF-β-induced cell migration, invasion, epithelial-mesenchymal-transition, and Smad phosphorylation in both cancer cell lines. Inhibition of PBR by PK11195 rescued the MDZ-inhibited cell proliferation, suggesting that MDZ worked through PBR to inhibit TGF-β pathway. Furthermore, MDZ inhibited proliferation, migration, invasion and levels of mesenchymal proteins in MDA-MD-231 triple-negative breast cancer cells. Together, MDZ inhibits cancer cell proliferation both in epithelial and mesenchymal types and EMT, indicating an important role for MDZ as a candidate to treat lung and breast cancers.

Effectiveness of Chloral Hydrate on Brain MRI in Children with Developmental Delay/Intellectual Disability Comparing with Normal Intelligence: Single Tertiary Center Experience

Neurodiagnostic investigation requirements are expanding for diagnostic and therapeutic purposes in children, especially in those with developmental delay/intellectual disability (DD/ID). Thus, determination of optimal sedatives to achieve successful sedation and immobility without further neurological compromise is important in children with DD/ID. The purpose of this study is to assess the effectiveness and adverse reactions of chloral hydrate (CH) for brain magnetic resonance imaging (B-MRI) in children with DD/ID compared to those with normal intelligence (NI). We performed a retrospective chart review of children aged from 1 day to 12 years who required elective sedation using CH for B-MRI. About 730 cases (415 with DD/ID and 315 with NI) of CH sedation were conducted for B-MRI. Children with DD/ID showed a higher failure rate (22%) than did those with NI (6%); additional CH and prolonged sedation time were required. There was no difference in incidence of adverse reactions between DD/ID and NI groups (p = 0.338). Older or heavier children with DD/ID (p = 0.036 and p = 0.013, respectively), as well as those diagnosed with epilepsy or neuropsychiatric disorders showed higher risk of sedation failure (p < 0.001 for each). In conclusion, CH was a suboptimal sedative drug for children with DD/ID compared with those with NI. Other alternative or supplementary sedatives should be taken into consideration especially for those vulnerable groups.

Dexmedetomidine Promotes Lipopolysaccharide-Induced Differentiation of Cardiac Fibroblasts and Collagen I/III Synthesis through α2A Adrenoreceptor-Mediated Activation of the PKC-p38-Smad2/3 Signaling Pathway in Mice

Dexmedetomidine (DEX), a selective α2 adrenergic receptor (AR) agonist, is commonly used as a sedative drug during critical illness. In the present study, we explored a novel accelerative effect of DEX on cardiac fibroblast (CF) differentiation mediated by LPS and clarified its potential mechanism. LPS apparently increased the expression of α-SMA and collagen I/III and the phosphorylation of p38 and Smad-3 in the CFs of mice. These effects were significantly enhanced by DEX through increasing α2A-AR expression in CFs after LPS stimulation. The CFs from α2A-AR knockout mice were markedly less sensitive to DEX treatment than those of wild-type mice. Inhibition of protein kinase C (PKC) abolished the enhanced effects of DEX on LPS-induced differentiation of CFs. We also found that the α-SMA level in the second-passage CFs was much higher than that in the nonpassage and first-passage CFs. However, after LPS stimulation, the TNF-α released from the nonpassage CFs was much higher than that in the first- and second-passage CFs. DEX had no effect on LPS-induced release of TNF-α and IL-6 from CFs. Further investigation indicated that DEX promoted cardiac fibrosis and collagen I/III synthesis in mice exposed to LPS for four weeks. Our results demonstrated that DEX effectively accelerated LPS-induced differentiation of CFs to myofibroblasts through the PKC-p38-Smad2/3 signaling pathway by activating α2A-AR.

The Availability and Safety Study of Remimazolam Besylate for Injection on Sedation of ERAS Patients Under Mechanical Ventilation in ICU: Protocol for a Randomized, Open-Label, Controlled Trial

Introduction: The most common physiological and psychological disorders associated with critical care patients are pain and anxiety. Sedatives and analgesics are commonly used to relieve these symptoms. However, the adverse effects of sedatives and analgesics are common and inevitable. As a new type of sedative drug, limited number of trials are available to evaluate Remimazolam Besylate's availability and safety compared with propofol.Methods: This study is a single center, randomized, open-label, controlled trial. A total of 84 patients who meet ERAS criteria and receive mechanical ventilation in ICU, aged ≥18 years old will be included. Patients will be randomized (1:1) into two groups: Remimazolam Besylate group and Propofol group. The Primary outcomes includes satisfaction rate of sedation and incidence rate of major clinical events. Secondary outcomes including incidence of delirium, time to weaning and extubation, Difficulty of nursing RASS, BIS and PI, 28-days survival, side-effect and vital signs during medications, total dose and dose per kilogram body weight of analgesic and sedatives and incidence of rescue therapy in experimental group.Ethics and Dissemination: This trial has been approved by the ethics boards of Peking Union Medical College Hospital. Recruitment began in January 2022 and will continue until June 2022. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT04947345

Abuse potential assessment of the new dual orexin receptor antagonist daridorexant in recreational sedative drug users as compared to suvorexant and zolpidem

Study Objectives Abuse potential properties have been reported for the dual orexin receptor antagonists (DORAs) suvorexant and lemborexant. Daridorexant is a new DORA currently in late-stage clinical development. This randomized, double-blind, double-dummy, placebo- and active-controlled 6-period crossover study assessed its abuse potential in healthy recreational sedative drug users (n=63). Methods In each study period, a single, oral, morning dose of either daridorexant (50, 100, 150 mg), placebo, or active control, i.e., suvorexant (150 mg) or zolpidem (30 mg), was administered. Primary pharmacodynamic endpoint was the Emax of the Drug-liking visual analog scale (VAS) assessed over 24 h. Several secondary subjective and objective pharmacodynamic endpoints were also assessed. Results Study validity was confirmed based on drug-liking of suvorexant and zolpidem greater than placebo applying a pre-defined 15-point validity margin (p&lt;0.0001). Drug-liking VAS Emax (mean; 95% CI) of daridorexant at 50 mg (73.2; 69.0-77.5) was significantly lower compared to suvorexant (80.7; 77.0-84.5) and zolpidem (79.9; 76.2-83.5) (p&lt;0.001), but similar at 100 mg (79.1; 75.0-83.3) and 150 mg (81.3; 77.7, 84.8). Such dose-related patterns were also observed for most secondary endpoints. At each daridorexant dose, Drug-liking VAS scores were greater than placebo. Both control drugs and daridorexant were safe and the pharmacokinetics of daridorexant was consistent with earlier trials indicating quick absorption and elimination. Conclusions In this large, valid human abuse potential study, daridorexant showed dose-related drug-liking among recreational sedative drug users with lower effects at the highest phase-3 dose, and similar effects at higher doses compared to supratherapeutic doses of suvorexant and zolpidem.

Relationship between the national institutes health stroke scale score and bispectral index in patients with acute ischemic stroke

This study aimed to investigate the relationship between the bispectral index and the National Institutes of Health Stroke Scale (NIHSS) score in patients admitted to the emergency department with a first-time acute ischemic stroke. Methods: This prospective, observational study was conducted with patients admitted to our clinic with acute ischemic stroke symptoms. Patients with known cranial pathologies, such as space- occupying lesions, those with a history of clinically significant cerebrovascular events or sedative drug administration, and those with altered consciousness due to metabolic causes were excluded from the study. The National Institutes Health Stroke Scale scores were recorded by the clinician. Cerebral arterial territories were assessed on DWI and CT. The relationship between the NIHSS score and bispectral index was evaluated. Results: Forty-three patients were included in the study. The mean bispectral index of the cases was 84.23 ± 9.50. There was no significant correlation between the bispectral index values and the NIHSS score (p<0.05). Conclusion: In our study, the bispectral index values were decreased due to ischemic stroke. The results should be reevaluated studies conducted with larger series to reveal the relationship between infarcted territories, NIHSS score, bispectral index, and the GCS score.