Midazolam-Induced Seizure-Like Activity in Five Neonates: A case series.

An intravenous (IV) administration of midazolam may result in seizure-like activity or movement. This report describes 5 neonates who developed seizure-like movements after IV midazolam injection. The patients presented between 2019 and 2022 and were admitted to a neonatal intensive care unit located within an academic centre in Muscat, Oman. The abnormal movements occurred shortly after IV bolus administration of midazolam. None of the patients experienced seizure-like movements after receiving midazolam infusions. The seizure-like movements were aborted either spontaneously or by antiseizure medications. In addition, seizure recurrence was not observed in any of the infants during the later stages of their treatment. Since this adverse effect might be related to the speed of the bolus administration, IV midazolam must be given as a slow bolus over 2-3 minutes followed by a slow flush of normal saline. To prevent midazolam's potential adverse effect on newborns, neonatal caregivers must be aware of it.

Discovery, synthesis and SAR of 2-acyl-1-biarylmethyl pyrazolidines, dual orexin receptor antagonists designed as fast and short-acting sleeping drugs.

Dual orexin receptor antagonists (DORAs) are approved for the treatment of sleep onset and/or sleep maintenance insomnia. In the present disclosure, we report the discovery of a new class of DORAs designed to treat sleep disorders requiring a fast onset and a short duration of action (<4 h). We used early human pharmacokinetic-pharmacodynamic (PK-PD) predictions and in vivo experiments to identify DORAs eliciting this specific hypnotic profile. A high-throughput screening campaign revealed hits based on a rarely precedented tricyclic pyrazolidine scaffold. After unsuccessful structure-activity-relationship (SAR) studies on this hit series, a scaffold hopping exercise, aimed at reducing the molecular complexity of the tricyclic scaffold, resulted in the discovery of the 2-acyl-1-biarylmethylpyrazolidine series. SAR studies on this achiral series gave rise to the lead compound DORA 42. In vitro and in vivo parameters of DORA 42, and its PK-PD simulation for human use are detailed.

Effects of a Triage Checklist to Optimize Insomnia Treatment Outcomes and Reduce Hypnotic Use: The RESTING Study.

STUDY OBJECTIVES: Evaluate a triaged stepped-care strategy among adults 50 and older with insomnia disorder. METHODS: Participants (N=245) were classified at baseline by a Triage-Checklist. Those projected to do better if they start treatment with therapist versus digitally delivered CBT-I (tCBT-I versus dCBT-I) constituted the YES stratum (n=137); the rest constituted the NO stratum (n=108). Participants were randomized within stratum to a strategy that utilized only dCBT-I (ONLN) or to a strategy that prospectively allocated the first step of care to dCBT-I or tCBT-I based on the Triage-Checklist and switched dCBT-I non-responders at 2-months to tCBT-I (STEP). Co-primary outcomes were the insomnia severity index (ISI) and the average nightly amount of prescription hypnotic medications used (MEDS), assessed at 2,4,6,9, and 12 months post-randomization. RESULTS: Mixed effects models revealed that, compared to ONLN, participants in STEP had greater reductions in ISI (p=0.001; η2=0.01) and MEDS (p=0.019, η2=0.01). Within the YES stratum, compared to ONLN, those in STEP had greater reductions in ISI (p=0.0001, η2=0.023) and MEDS (p=0.018, η2=0.01). Within the ONLN arm, compared to the YES stratum, those in the NO stratum had greater reductions in ISI (p=0.015, η2=0.01) but not in MEDS. Results did not change with treatment-dose covariate adjustment. CONCLUSIONS: Triaged-stepped care can help guide allocation of limited CBT-I treatment resources to promote effective and safe treatment of chronic insomnia among middle age and older adults. Further refinement of the Triage-Checklist and optimization of the timing and switching criteria may improve the balance between effectiveness and use of resources.

Changing patterns of hospitalization for sedative misuse among youth aged 10-24 years in Quebec, Canada.

Purpose: To assess trends in hospitalization for sedative misuse among youth. Methods: Using a serial cross-sectional design, we computed hospitalization rates for sedative-related suicide attempts, sedative use disorders, and other sedative poisonings within individuals aged 5-24 years in Quebec, Canada. We computed sedative-related hospitalization rates in 2006-2011, 2012-2017, and 2018-2023, and examined differences according to age, sex, polysubstance use, mental health comorbidity, and social vulnerability using rate ratios (RR) and 95 % confidence intervals (CI) comparing the last time period relative to the first. Results: Sedative-related hospitalization rates more than doubled during the study. Suicide attempts using sedatives increased from 50.5 per 100,000 youth in 2006-2011, to 82.2 in 2012-2017 and 114.4 in 2018-2023 (RR 2.26, 95 % CI 1.63-3.15), while sedative use disorders increased from 13.1 to 21.8 and 60.5 per 100,000 in these same time periods (RR 4.62, 95 % CI 2.54-8.40). Rates increased for 10-24 year-olds and in both sexes, particularly among youth with polysubstance use, anxiety and attention disorders, and social vulnerability. Discussion: Sedative misuse requiring hospitalization appears to be a growing issue among youth.

Effects of High-altitude Hypoxia on Drug Metabolism and Pharmacokinetics of Sedative-hypnotic Drugs and Regulatory Mechanism.

Sedative hypnotics effectively improve sleep quality under high-altitude hypoxia by reducing central nervous system excitability. High-altitude hypoxia causes sleep disorders and modifies the metabolism and mechanisms of drug action, impacting medication therapy's effectiveness. This review aims to provide a theoretical basis for the treatment of central nervous system diseases in high-altitude areas by summarizing the progress and mechanism of sedative-hypnotics in hypoxic environments, as well as the impact of high-altitude hypoxia on sleep.

Evaluation of prescribing patterns of switching to and add-on lemborexant in patients treated with hypnotic medication: a nationwide claims database study in Japan.

BACKGROUND: When considering changing hypnotic pharmacotherapy, lemborexant has attracted attention as a candidate due to its effectiveness and safety profile. However, few studies have investigated switching patterns in clinical practice. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study using a nationwide claims database. Patients prescribed a single hypnotic who either subsequently switched to (switching cohort) or were additionally prescribed (add-on cohort) lemborexant between July 2020 and December 2021 were identified. Proportion of successful switching was defined as remaining on lemborexant alone or without any hypnotic at 6 months after lemborexant initiation. RESULTS: The success proportion was 70.1% in the switching cohort (n = 4,861) and 38.6% in the add-on cohort (n = 9,423). In the add-on cohort, the success proportion was lower in patients with a hypnotic history of ≥180 days (31.4%) and in patients whose prescribed hypnotic was a benzodiazepine or non-benzodiazepine (31.5% and 37.6%, respectively). CONCLUSION: The proportion of successful switching was higher in patients who switched to lemborexant than in those who added lemborexant as a concomitant treatment. The lower success proportion in the add-on cohort might be related to clinically more severe insomnia, and/or a concomitant prescription of benzodiazepine or non-benzodiazepine, from which discontinuation may be challenging.

Comparing the Sedative Effects of Intranasal Dexmedetomidine, Midazolam, and Ketamine in Outpatient Pediatric Surgeries: A Randomized Clinical Trial.

Background: The management of preoperative anxiety in pediatric patients, as well as its implications, has remained challenging for anesthesiologists. In this study, we compared the safety and efficacy of intranasal dexmedetomidine, midazolam, and ketamine as surgical premedication in children. Methods: This double-blinded randomized clinical trial was conducted at two tertiary hospitals in January 2014, on 90 children aged between 2-7 years old. The participants' American Society of Anesthesiologists (ASA) physical status was I or II, and they were scheduled for elective unilateral inguinal herniorrhaphy. Using the block randomization method, the patients were randomly assigned to three groups, each receiving intranasal dexmedetomidine (2 µg/Kg), midazolam (0.2 mg/Kg), and ketamine (8 mg/Kg) 60 min before induction of anesthesia. Anxiety and sedation state were evaluated before drug administration, and then every 10 min for the next 50 min. Parental separation anxiety, mask acceptance, postoperative agitation, pain, nausea, and vomiting were also recorded and compared between these groups. All the statistical analyses were performed using SPSS software (version 21.0). P<0.05 was considered statistically significant. Results: Ketamine indicated the strongest sedative effect 10, 20, and 30 min after administration of premedication (P<0.001, P=0.03, P=0.01, respectively). However, dexmedetomidine was more effective than other drugs after 40 and 50 min (P<0.001). Other variables indicated no statistically significant difference. Conclusion: In case of emergencies, intranasal ketamine, with the shortest time of action, could be administered. Intranasal dexmedetomidine, which was revealed to be the most potent drug in this study, could be administrated 40-50 min before elective pediatric surgeries.Trial registration number: IRCT2013081614372N1.

Factors associated with hypnotics polypharmacy in the Japanese population.

OBJECTIVE: Insomnia disorder is a global public health issue, commonly treated with hypnotics. However, long-term use of benzodiazepine derivatives (BZDs), especially polypharmacy with this kind of drug, carries risks for dependence and abuse. This study using large-scale medical insurance records investigated the causes of polypharmacy through the treatment of insomnia disorder. METHODS: A cross-sectional study analyzed anonymized medical record data from July 2014 to March 2018 provided by a nationwide Japanese health insurance association covering 405,952 individuals. Outpatients prescribed at least one sleep medication were included. Demographic data, pharmacological classification of the drugs, and comorbidities were assessed using hierarchical logistic regression analysis to explore their associations with polypharmacy. RESULTS: Of the 33,212 outpatients who were prescribed sleep medications, 32.5 % were prescribed multiple types. After adjusting for demographics and type of sleep medications as covariates, hypnotic polypharmacy was significantly associated with younger age, the presence of certain kinds of comorbidities, and using BZD anxiolytics before bedtime with the highest adjusted odds ratios (8.01-9.39) when referenced with BZD hypnotics. On the other hand, usage of orexin receptor antagonists, melatonin receptor agonists, and Z-drugs indicated lower odds ratios (0.74-0.87). CONCLUSIONS: Hypnotic polypharmacy is relatively common in the Japanese general population. With the introduction of non-pharmacological therapy in mind, assessing patients' comorbidities and avoiding the use of benzodiazepines, especially BZD anxiolytics, before bedtime would be recommended to prevent polypharmacy.

Neurexan Prescription Is Associated with Lower Risk of Sleep Disorder Recurrence and Depression Prevalence as Compared to Z-Drugs and Benzodiazepines: A Retrospective Database Analysis in Germany.

Real-world evidence on the association between natural medicinal products and the recurrence of sleep disorders is currently limited, particularly when compared to the evidence reported for prescription hypnotics. In a retrospective cohort analysis, we investigated patients with sleep disorders prescribed either the natural medicinal product Neurexan (Nx4), benzodiazepines, or nonbenzodiazepines (Z-drugs) using the IQVIA Disease Analyzer database, which encompasses electronic medical records nationwide in Germany. A 1:1 matching procedure based on age, sex, prevalent depression, anxiety or adjustment disorder, and the number of medical consultations in the past 12 months resulted in four cohorts: patients prescribed Nx4 were matched with those prescribed Z-drugs (two cohorts with 8594 matched patients each), and another cohort of patients prescribed Nx4 were matched with those prescribed benzodiazepines (7779 matched pairs). Results from multivariable-adjusted Cox regression models demonstrated that Nx4 was associated with a significantly lower risk of recurrent sleep disorder diagnosis within 30-365 days after prescription compared to both Z-drugs (HR = 0.65, 95%CI = 0.60-0.70, p < 0.001) and benzodiazepines (HR = 0.85, 95%CI = 0.79-0.93, p < 0.001). Additionally, Nx4 was associated with a lower prevalence of depression compared to Z-drugs (HR = 0.90, 95%CI = 0.83-0.98, p = 0.020) and benzodiazepines (HR = 0.89, 95%CI = 0.82-0.97, p = 0.009). These findings suggest an association between Nx4 and improved sleep and mental health outcomes. However, due to inherent limitations in the study design, the causality of this relationship cannot be stated.

Impact of cumulative exposure to anticholinergic and sedative drugs on cognition in older adults: a memory clinic cohort study.

BACKGROUND: Long-term exposure to anticholinergic and sedative drugs could be a modifiable risk factor for cognitive decline. The objective of this study was to measure the association between previous cumulative anticholinergic and sedative drug exposure (Drug Burden Index) and cognitive decline. METHODS: A cohort study (MEMORA cohort) was conducted in a French memory clinic for patients attending a consultation between November 2014 and December 2020, with at least 2 Mini-Mental State Examination (MMSE) measurements (≥ 6 months apart) and available medication data from the local Primary Health Insurance Fund database (n = 1,970). Drug Burden Index was linearly cumulated until each MMSE measurement and was used to categorise patients according to their level of exposure (no exposure, moderate, or high). The longitudinal association between Drug Burden Index and MMSE was assessed using a multivariate linear mixed model, adjusted for age, education level, anxiety disorders, depressive disorders, functional autonomy, and behavioural disorders. RESULTS: Overall, 1,970 patients were included with a mean follow-up duration of 2.78 years (± 1.54) and 2.99 visits per patients (5,900 MMSE + Drug Burden Index measurements collected). At baseline, 68.0% of patients had moderate cumulative anticholinergic and sedative drug exposure and a mean MMSE of 21.1. MMSE decrease was steeper in patients with moderate and high Drug Burden Index ( -1.74 and -1.70/year, respectively) than in patients with no exposure (-1.26/year) after adjusting for age, education, anxiety and depressive disorders, functional autonomy, and behavioural disorders (p < 0.01). CONCLUSIONS: Long-term exposure to anticholinergic and sedative drugs is associated with steeper cognitive decline. Medication review focusing on de-prescribing these drugs could be implemented early to reduce cognitive impairment.

Non-benzodiazepine Hypnotics and Police-Reported Motor Vehicle Crash Risk among Older Adults: A Sequential Target Trial Emulation.

Non-benzodiazepine hypnotics ( "Z-drugs") are prescribed for insomnia, but might increase risk of motor vehicle crash (MVC) among older adults through prolonged drowsiness and delayed reaction times. We estimated the effect of initiating Z-drug treatment on the 12-week risk of MVC in a sequential target trial emulation. After linking New Jersey driver licensing and police-reported MVC data to Medicare claims, we emulated a new target trial each week (July 1, 2007 - October 7, 2017) in which Medicare fee-for-service beneficiaries were classified as Z-drug-treated or untreated at baseline and followed for an MVC. We used inverse probability of treatment and censoring weighted pooled logistic regression models to estimate risk ratios (RR) and risk differences with 95% bootstrap confidence limits (CLs). There were 257,554 person-trials, of which 103,371 were Z-drug-treated and 154,183 untreated, giving rise to 976 and 1,249 MVCs, respectively. The intention-to-treat RR was 1.06 (95%CLs 0.95, 1.16). For the per-protocol estimand, there were 800 MVCs and 1,241 MVCs among treated and untreated person-trials, respectively, suggesting a reduced MVC risk (RR 0.83 [95%CLs 0.74, 0.92]) with sustained Z-drug treatment. Z-drugs should be prescribed to older patients judiciously but not withheld entirely over concerns about MVC risk.

Driving performance of long-term users of sedating antidepressants and benzodiazepines.

OBJECTIVE: Using benzodiazepines and certain antidepressants is associated with an increased risk of motor vehicle crashes due to impaired driving skills. Hence, several countries prohibit people who use these drugs from driving. Traffic regulations for driving under the influence of these drugs are, however, largely based on single-dose studies with healthy participants. The effects of drugs on chronic users may be different because of potential development of tolerance or by adapting behavior. In this study, we test the effects of anti-depressants, hypnotics, or anxiolytics use on driving performance in patients who use these drugs for different durations and compare the effects to healthy controls' performance. METHODS: Sixty-six healthy controls and 82 medication users were recruited to perform four drives in a driving simulator. Patients were divided into groups that used anti-depressants, hypnotics, or anxiolytics, for shorter or longer than 3 years (i.e. LT3- or LT3+, respectively). The minimum term of use was 6 months. Driving behavior was measured in terms of longitudinal and lateral control (speed variability and Standard Deviation of Lateral Position: SDLP), brake reaction time, and time headway. Impaired driving performance was defined as performing similar to driving with a Blood Alcohol Concentration of 0.5‰ or higher, determined by means of non-inferiority analyses. RESULTS: Reaction time analyses revealed inconclusive findings in all groups. No significant performance differences between matched healthy controls, LT3- (n = 2), and LT3+ (n = 8) anxiolytics users were found. LT3+ antidepressants users (n = 12) did not perform inferior to their matched controls in terms of SDLP. LT3- hypnotics users (n = 6) showed more speed variability than their matched healthy controls, while this effect was not found for the LT3+ group (n = 14): the latter did not perform inferior to the healthy controls. Regarding Time Headway, no conclusions about the LT3- hypnotics group could be drawn, while the LT3+ group did not perform inferior compared to the control group. CONCLUSIONS: The small number of anxiolytics users prohibits drawing conclusions about clinical relevance. Although many outcomes were inconclusive, there is evidence that some elements of complex driving performance may not be impaired (anymore) after using antidepressants or hypnotics longer than 3 years.

Red-Haired People's Altered Responsiveness to Pain, Analgesics, and Hypnotics: Myth or Fact?-A Narrative Review.

Red hair has been linked to altered sensitivity to pain, analgesics, and hypnotics. This alteration may be impacted by variants in the melanocortin-1 receptor (MC1R) gene, which are mainly found in redheads. The aim of this narrative review was to explore and present the current state of knowledge on red hair and its plausible associations with altered responsiveness to pain, analgesics, and hypnotics. Structured searches in the PubMed, CINAHL Complete, and Scopus electronic databases were conducted. Evidence suggests that women with red hair have an increased sensitivity to pain. Conversely, data also indicate a higher pain tolerance in homozygous carriers of MC1R variant alleles. Varied responses to analgesia have been reported, with both increased analgesic responsiveness in homozygous carriers of MC1R variant alleles and less analgesia in redheads. Data indicate an increased need for hypnotics in redheads. However, failed attempts to find statistical associations between red hair and altered responsiveness to hypnotics are also evident. Even though there seems to be an association between red hair and an altered responsiveness to pain, analgesics, and/or hypnotics, the results of this narrative review are inconclusive. Further research studies with larger populations and MC1R testing are needed.

Optimizing the Time and Dose of Melatonin as a Sleep-Promoting Drug: A Systematic Review of Randomized Controlled Trials and Dose-Response Meta-Analysis.

Previous studies have reported inconsistent results about exogenous melatonin's sleep-promoting effects. A possible explanation relies on the heterogeneity in administration schedule and dose, which might be accountable for differences in treatment efficacy. In this paper, we undertook a systematic review and meta-analysis of double-blind, randomized controlled trials performed on patients with insomnia and healthy volunteers, evaluating the effect of melatonin administration on sleep-related parameters. The standardized mean difference between treatment and placebo groups in terms of sleep onset latency and total sleep time were used as outcomes. Dose-response and meta-regression models were estimated to explore how time of administration, dose, and other treatment-related parameters might affect exogenous melatonin's efficacy. We included 26 randomized controlled trials published between 1987 and 2020, for a total of 1689 observations. Dose-response meta-analysis showed that melatonin gradually reduces sleep onset latency and increases total sleep time, peaking at 4 mg/day. Meta-regression models showed that insomnia status (ß = 0.50, p < 0.001) and time between treatment administration and the sleep episode (ß = -0.16, p = 0.023) were significant predictors of sleep onset latency, while the time of day (ß = -0.086, p < 0.01) was the only significant predictor of total sleep time. Our results suggest that advancing the timing of administration (3 h before the desired bedtime) and increasing the administered dose (4 mg/day), as compared to the exogenous melatonin schedule most used in clinical practice (2 mg 30 min before the desired bedtime), might optimize the efficacy of exogenous melatonin in promoting sleep.

Global trend of nondrug and nonsedativehypnotic treatment forinsomnia: a bibliometric study.

OBJECTIVE: To present a bibliometric analysis of global scientific publications on the nondrug and nonsedative hypnotic treatment of insomnia with regard to influential institutions, publications, countries, research hotspots, trends, and frontiers. METHODS: A literature review was conducted by searching the Web of Science Core Collection (WoSCC) and China National Knowledge Infrastructure (CNKI) databases to identify all publications related to the nondrug and nonsedative hypnotic treatment of insomnia from 2000 to 2021. Eligible publications were reviewed, including annual publication increments, citation analyses, international collaborations, and keyword analyses. The data were analysed using CiteSpace (vers5.8.R3, 6.1.R2 and 6.1.6, College of Computing and Informatics, Philadelphia, PA, USA) and virtualized by knowledge maps. RESULTS：In total, 9832 publications were included in this analysis. The results from the WoSCC showed that the United States of America (Count = 2268, 40.33%), Stanford University (Count = 141, 2.51%), and the United States Department of Health and Human Services were the leading country, institute, and funding agency regarding the number of publications, respectively. 'Cognitive-behavioural therapy" was the most popular research topic generated from the cocited reference. The most frequently co-occurring keywords were insomnia, cognitive behavioural therapy, disorder, depression, quality of life, Meta-analysis, older adult, sleep, prevalence and efficacy, while keywords including clinical practice guideline, guideline, and Tai Chi remained popular after 2021. Circadian rhythm was the strongest research frontier for 2000-2021. In China, Chengdu University of Traditional Chinese Medicine (Count = 69, 4.79%) was the most productive institute in this field. The most frequently co-occurring keywords from Chinese literature were sleep disorder, sleep quality, acupuncture and moxibustion, Parkinson's disease, transcranial magnetic stimulation, health education, music therapy, chronic insomnia, quality of life, and nonmotor symptoms. Traditional Chinese medicine was the strongest research frontier for 2019-2021. CONCLUSION: This bibliometric study provides an exhaustive mapping encompassing pertinent institute, publications, influential articles, researchers and topics of the global trend of nondrug and nonsedative hypnotic treatment for insomnia. The results show that the research trend has shifted from primary studies on the efficacy and safety of nondrug and nonsedative hypnotic treatment for insomnia to comorbidity studies. Clinical practice guidelines will potentially become the research frontier for this field post-2021. The findings are important for researchers, clinicians, journal editors, and policy-makers working in the field of nondrug and nonsedative hypnotic treatment for insomnia to understand the strengths and potentials in the current studies and guide future clinical practice, research, and science policy.

Insomnia, Short Sleep, and Their Treatments: Review of Their Associations with Weight.

PURPOSE OF REVIEW: Insomnia and short sleep have been linked with weight gain and obesity. However, these findings have not been consistent across studies. We review recent evidence for the association between insomnia, short sleep, and weight gain, as well as the relationship between behavioral and pharmacological treatments for sleep and weight. RECENT FINDINGS: The relationship between insomnia and obesity is mixed, with stronger associations between insomnia with short sleep and obesity than other presentations of insomnia. Short sleep is associated with weight gain. Z-drugs and benzodiazapines do not appear to impact weight, but many antidepressants and antipsychotics that are used for insomnia treatment do cause weight gain. The relationships between insomnia and short sleep with weight gain and obesity are inconsistent. More prospective trials are needed to identify mediators and moderators of this relationship to better develop and deliver effective interventions for both sleep and weight problems.

Association Between Hypnotics and Dementia: A Mini Narrative Review.

OBJECTIVE: This narrative review aims to provide a comprehensive assessment of the existing literature on the relationship between hypnotics and dementia, considering both potential link and inconclusive or lack of association. METHODS: Data from studies that investigate the association between hypnotic medications and dementia were reviewed. Studies included both cohort studies and systematic reviews, participants with various type of dementia and hypnotics including benzodiazepines (BZDs) and Z-drugs (ZDs). RESULTS: The existing literatures presents conflicting evidence regarding the association between hypnotics, including BZDs and ZDs, and the risk of dementia. Some studies suggest a potential link between prolonged use of hypnotics and an increased risk of dementia. However, other studies indicate inconclusive or lacking evidence regarding this association. Factors such as study design, sample characteristics, and control of confounding variables contribute to the variability in findings. CONCLUSION: The relationship between hypnotics and dementia remains complex and controversial. While some studies suggest a potential association, others find inconclusive or conflicting evidence. Future research should focus on addressing methodological limitations, considering classifying dementia subtypes, and try to adjust medication lag time.

Insomnia-related rodent models in drug discovery.

Despite the widespread prevalence and important medical impact of insomnia, effective agents with few side effects are lacking in clinics. This is most likely due to relatively poor understanding of the etiology and pathophysiology of insomnia, and the lack of appropriate animal models for screening new compounds. As the main homeostatic, circadian, and neurochemical modulations of sleep remain essentially similar between humans and rodents, rodent models are often used to elucidate the mechanisms of insomnia and to develop novel therapeutic targets. In this article, we focus on several rodent models of insomnia induced by stress, diseases, drugs, disruption of the circadian clock, and other means such as genetic manipulation of specific neuronal activity, respectively, which could be used to screen for novel hypnotics. Moreover, important advantages and constraints of some animal models are discussed. Finally, this review highlights that the rodent models of insomnia may play a crucial role in novel drug development to optimize the management of insomnia.

Development of a predictive model for hypoxia due to sedatives in gastrointestinal endoscopy: a prospective clinical study in Korea.

BACKGROUND/AIMS: Sedation has become a standard practice for patients undergoing gastrointestinal (GI) endoscopy. However, considering the serious cardiopulmonary adverse events associated with sedatives, it is important to identify patients at high risk. Machine learning can generate reasonable prediction for a wide range of medical conditions. This study aimed to evaluate the risk factors associated with sedation during GI endoscopy and develop a predictive model for hypoxia during endoscopy under sedation. METHODS: This prospective observational study enrolled 446 patients who underwent sedative endoscopy at the Korea University Ansan Hospital. Clinical data were used as predictor variables to construct predictive models using the random forest method that is a machine learning algorithm. RESULTS: Seventy-two of the 446 patients (16.1%) experienced life-threatening hypoxia requiring immediate medical intervention. Patients who developed hypoxia had higher body weight, body mass index (BMI), neck circumference, and Mallampati scores. Propofol alone and higher initial and total dose of propofol were significantly associated with hypoxia during sedative endoscopy. Among these variables, high BMI, neck circumference, and Mallampati score were independent risk factors for hypoxia. The area under the receiver operating characteristic curve for the random forest-based predictive model for hypoxia during sedative endoscopy was 0.82 (95% confidence interval, 0.79-0.86) and displayed a moderate discriminatory power. CONCLUSIONS: High BMI, neck circumference, and Mallampati score were independently associated with hypoxia during sedative endoscopy. We constructed a model with acceptable performance for predicting hypoxia during sedative endoscopy.

Respiratory drive heterogeneity associated with systemic inflammation and vascular permeability in acute respiratory distress syndrome.

BACKGROUND: In acute respiratory distress syndrome (ARDS), respiratory drive often differs among patients with similar clinical characteristics. Readily observable factors like acid-base state, oxygenation, mechanics, and sedation depth do not fully explain drive heterogeneity. This study evaluated the relationship of systemic inflammation and vascular permeability markers with respiratory drive and clinical outcomes in ARDS. METHODS: ARDS patients enrolled in the multicenter EPVent-2 trial with requisite data and plasma biomarkers were included. Neuromuscular blockade recipients were excluded. Respiratory drive was measured as PES0.1, the change in esophageal pressure during the first 0.1 s of inspiratory effort. Plasma angiopoietin-2, interleukin-6, and interleukin-8 were measured concomitantly, and 60-day clinical outcomes evaluated. RESULTS: 54.8% of 124 included patients had detectable respiratory drive (PES0.1 range of 0-5.1 cm H2O). Angiopoietin-2 and interleukin-8, but not interleukin-6, were associated with respiratory drive independently of acid-base, oxygenation, respiratory mechanics, and sedation depth. Sedation depth was not significantly associated with PES0.1 in an unadjusted model, or after adjusting for mechanics and chemoreceptor input. However, upon adding angiopoietin-2, interleukin-6, or interleukin-8 to models, lighter sedation was significantly associated with higher PES0.1. Risk of death was less with moderate drive (PES0.1 of 0.5-2.9 cm H2O) compared to either lower drive (hazard ratio 1.58, 95% CI 0.82-3.05) or higher drive (2.63, 95% CI 1.21-5.70) (p = 0.049). CONCLUSIONS: Among patients with ARDS, systemic inflammatory and vascular permeability markers were independently associated with higher respiratory drive. The heterogeneous response of respiratory drive to varying sedation depth may be explained in part by differences in inflammation and vascular permeability.