In Vitro Hepatotoxicity of Routinely Used Opioids and Sedative Drugs.

A hepatocyte cell line was used to determine the hepatotoxicity of sedatives and opioids, as the hepatotoxicity of these drugs has not yet been well characterized. This might pose a threat, especially to critically ill patients, as they often receive high cumulative doses for daily analgosedation and often already have impaired liver function due to an underlying disease or complications during treatment. A well-established biosensor based on HepG2/C3A cells was used for the determination of the hepatotoxicity of commonly used sedatives and opioids in the intensive care setting (midazolam, propofol, s-ketamin, thiopental, fentanyl, remifentanil, and sufentanil). The incubation time was 2 × 3 days with clinically relevant (Cmax) and higher concentrations (C5× and C10×) of each drug in cell culture medium or human plasma. Afterward, we measured the cell count, vitality, lactate dehydrogenase (LDH), mitochondrial dehydrogenase activity, cytochrome P 450 1A2 (CYP1A2), and albumin synthesis. All tested substances reduced the viability of hepatocyte cells, but sufentanil and remifentanil showed more pronounced effects. The cell count was diminished by sufentanil in both the medium and plasma and by remifentanil only in plasma. Sufentanil and remifentanil also led to higher values of LDH in the cell culture supernatant. A reduction of mitochondrial dehydrogenase activity was seen with the use of midazolam and s-ketamine. Microalbumin synthesis was reduced in plasma after its incubation with higher concentrations of sufentanil and remifentanil. Remifentanil and s-ketamine reduced CYP1A2 activity, while propofol and thiopental increased it. Our findings suggest that none of the tested sedatives and opioids have pronounced hepatotoxicity. Sufentanil, remifentanil, and s-ketamine showed moderate hepatotoxic effects in vitro. These drugs should be given with caution to patients vulnerable to hepatotoxic drugs, e.g., patients with pre-existing liver disease or liver impairment as part of their underlying disease (e.g., hypoxic hepatitis or cholestatic liver dysfunction in sepsis). Further studies are indicated for this topic, which may use more complex cell culture models and global pharmacovigilance reports, addressing the limitation of the used cell model: HepG2/C3A cells have a lower metabolic capacity due to their low levels of CYP enzymes compared to primary hepatocytes. However, while the test model is suitable for parental substances, it is not for toxicity testing of metabolites.

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.

Trends in hypnotic drug use in depression 2007-2017: A Swedish population-based study.

Insomnia is a common feature of depression; however, depression treatment guidelines provide limited recommendations regarding hypnotic drugs. Few studies have thoroughly investigated the use of hypnotic drugs in depression. In this cohort study using national Swedish registers, we included all patients ≥18 years with incident unipolar depression during 2007-2017. Patients were followed for 3 years, noting the annual and quarterly prevalence of hypnotic drug use from prescription fills. Prevalence ratios (PR) comparing 2017 to 2007 were calculated with 95% confidence intervals (CI). A total of 222,077 patients with depression were included (mean age 41 years, 59% women). In the year following diagnosis, 44.1% used any hypnotic drug in 2017, compared with 46.7% in 2007 (PR 0.94, 95% CI 0.92-0.97). The most commonly used drugs were Z-drugs (zopiclone, zolpidem, and zaleplon) with a prevalence of 27.6% in 2017 and 35.6% in 2007 (PR 0.78, 95% CI 0.75-0.80). Melatonin use increased sharply to 12.0% in 2017 from 0.4% in 2007 (PR 28.9, 95% CI 23.5-35.7). Hypnotic drug use was most prevalent in the first two quarters after diagnosis; however, after 3 years, the quarterly prevalence was still 19.2%. Hypnotics were more common among women, older patients, those with somatic comorbidities, more severe depression, or a history of suicide attempt. Evidence from this large register-based study demonstrates that hypnotics were used to a large extent in depression in Sweden 2007-2017. Z-drugs use declined and melatonin use increased dramatically. Hypnotic drug use remained high even 3 years after diagnosis.

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.

Evaluation of Clinical Outcomes Associated With Phenobarbital With Taper Compared to No Taper for the Management of Alcohol Withdrawal Syndrome.

BACKGROUND: Phenobarbital (PHB) has been shown to be an effective treatment of alcohol withdrawal syndrome (AWS), with multiple dosing strategies used (e.g., single-dose and symptom-triggered). Studies have often used tapered doses, typically following a front-loaded dose, despite PHB's long half-life which should lead to an ability to auto-taper. OBJECTIVE: The purpose of this study was to compare clinical outcomes associated with two PHB dosing strategies (taper [T], no taper [NT]) for AWS. METHODS: This retrospective cohort study compared adult patients admitted to the ICU from October 2017 to May 2019 who received an initial loading dose of PHB for AWS. The use of PHB was at the discretion of the clinician per our institutional guidelines. Prior to November 2018, patients were prescribed a PHB taper, while after this period, the taper was no longer recommended. The primary outcome was the proportion of patients requiring rescue PHB or adjunctive medications for AWS. Secondary outcomes included number of adjunctive agents used, prevalence of severe manifestations of AWS, ICU and hospital lengths of stay, and incidence of potentially significant drug interactions. RESULTS: A total of 172 patients were included (T: n = 81, NT: n = 91). Baseline characteristics were similar between groups, including history of severe AWS and cumulative benzodiazepine dose pre-PHB. There was no difference in the primary outcome between groups (T: 70.4% vs NT: 59.3%, P = 0.152). The median number of adjunctive agents per patient, severe manifestations, and ICU and hospital length of stay did not differ between groups. Twenty-five patients (14.5%) had potentially significant drug interactions. CONCLUSION AND RELEVANCE: The use of a PHB loading dose without a taper may be comparable to a taper strategy on clinical outcomes. Prospective studies are needed to further delineate the optimal dose of PHB for AWS.

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.

Exposure to Sedation and Analgesia Medications: Short-term Cognitive Outcomes in Pediatric Critical Care Survivors With Acquired Brain Injury.

Background/Objective: Pediatric intensive care unit (PICU) survivors risk significant cognitive morbidity, particularly those with acquired brain injury (ABI) diagnoses. Studies show sedative and analgesic medication may potentiate neurologic injury, but few studies evaluate impact on survivor outcomes. This study aimed to evaluate whether exposures to analgesic and sedative medications are associated with worse neurocognitive outcome. Methods: A retrospective cohort study was conducted of 91 patients aged 8 to 18 years, undergoing clinical neurocognitive evaluation approximately 1 to 3 months after PICU discharge. Electronic health data was queried for sedative and analgesic medication exposures, including opioids, benzodiazepines, propofol, ketamine, and dexmedetomidine. Doses were converted to class equivalents, evaluated by any exposure and cumulative dose exposure per patient weight. Cognitive outcome was derived from 8 objective cognitive assessments with an emphasis on executive function skills using Principal Components Analysis. Then, linear regression was used to control for baseline cognitive function estimates to calculate a standardized residualized neurocognitive index (rNCI) z-score. Multivariable linear regression evaluated the association between rNCI and medication exposure controlling for covariates. Significance was defined as P < .05. Results: Most (n = 80; 88%) patients received 1 or more study medications. Any exposure and higher cumulative doses of benzodiazepine and ketamine were significantly associated with worse rNCI in bivariate analyses. When controlling for Medicaid, preadmission comorbid conditions, length of stay, delirium, and receipt of other medication classes, receipt of benzodiazepine was associated with significantly worse rNCI (ß-coefficient = -0.48, 95% confidence interval = -0.88, -0.08). Conclusions: Exposure to benzodiazepines was independently associated with worse acute phase cognitive outcome using objective assessments focused on executive function skills when controlling for demographic and illness characteristics. Clinician decisions regarding medication regimens in the PICU may serve as a modifiable factor to improve outcomes. Additional inquiry into associations with long-term cognitive outcome and optimal medication regimens is needed.

Effective remimazolam loading dose for adequate sedation in regional anesthesia.

PURPOSE: Remimazolam is a novel ultrashort-acting sedative considered appropriate for continuous infusion during surgical procedures. Nevertheless, information regarding its loading dose for sedation during surgery is limited. We aimed to determine the 90% effective dose (ED90) of the remimazolam loading dose for sedation in patients undergoing limb surgery under regional anesthesia. METHODS: We included 50 patients aged 19-80 yr undergoing limb surgery under regional anesthesia. After regional anesthesia, remimazolam besylate was administered at the assigned dose. For ten minutes after the initiation of loading, the level of sedation was evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. The primary outcome was the ED90 based on whether patients reached a MOAA/S score of ≤ 3 points (loss of response to verbal command) within ten minutes. The secondary outcomes were the ED50 and the estimated effect site and plasma concentration at the time of achieving successful sedation. RESULTS: In total, 49 patients were included in the final analysis, and adequate sedation with the assigned loading dose was successful in 42 patients. The log-logistic function showed that the ED90 and ED50 were 0.617 mg·kg-1·hr-1 (95% confidence interval [CI], 0.511 to 0.722; 98% CI, 0.492 to 0.741) and 0.438 mg·kg-1·hr-1 (95% CI, 0.335 to 0.541; 98% CI, 0.315 to 0.560), respectively. CONCLUSION: The ED90 of the remimazolam loading dose to achieve adequate sedation in patients undergoing limb surgery under regional anesthesia was 0.617 mg·kg-1·hr-1 (95% CI, 0.511 to 0.722; 98% CI, 0.492 to 0.741). STUDY REGISTRATION: ClinicalTrials.gov (NCT05340335); first posted 22 April 2022.

RéSUMé: OBJECTIF: Le remimazolam est un nouveau sédatif à action ultracourte considéré comme approprié pour la perfusion continue pendant les interventions chirurgicales. Néanmoins, les informations concernant sa dose de charge pour la sédation pendant la chirurgie sont limitées. Notre objectif était de déterminer la dose efficace à 90 % (DE90) de la dose de charge de remimazolam pour la sédation chez la patientèle bénéficiant d'une chirurgie d'un membre sous anesthésie régionale. MéTHODE: Cinquante personnes âgées de 19 à 80 ans bénéficiant d'une chirurgie des membres sous anesthésie régionale ont été incluses. Après l'anesthésie régionale, du bésylate de remimazolam a été administré à la dose assignée. Pendant dix minutes après le début de la charge, le niveau de sédation a été évalué à l'aide de l'échelle modifiée d'évaluation de la vigilance/sédation par l'observateur (MOAA/S). Le critère d'évaluation principal était la DE90 selon que les patient·es ont atteint un score MOAA/S de ≤ 3 points (perte de réponse à la commande verbale) dans les dix minutes. Les critères d'évaluation secondaires étaient la DE50 et l'estimation du site d'effet et de la concentration plasmatique au moment de l'obtention d'une sédation réussie. RéSULTATS: Au total, 49 personnes ont été incluses dans l'analyse finale, et une sédation adéquate avec la dose de charge assignée a été couronnée de succès chez 42 d'entre elles. La fonction log-logistique a montré que les DE90 et DE50 étaient de 0,617 mg·kg−1·h−1 (intervalle de confiance [IC] à 95 %, 0,511 à 0,722; IC 98 %, 0,492 à 0,741) et 0,438 mg·kg−1·h−1 (IC 95 %, 0,335 à 0,541; IC 98 %, 0,315 à 0,560), respectivement. CONCLUSION: La DE90 de la dose de charge de remimazolam pour obtenir une sédation adéquate chez les personnes bénéficiant d'une chirurgie des membres sous anesthésie régionale était de 0,617 mg·kg−1·h−1 (IC 95 %, 0,511 à 0,722; IC 98 %, 0,492 à 0,741). ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT05340335); première publication le 22 avril 2022.

[Safe discontinuation of psychotropic drugs in older people? : New evidence and practical approach]. / Sicheres Absetzen von Psychopharmaka bei älteren Menschen? : Neue Evidenz und praktisches Vorgehen.

BACKGROUND: Many older patients are permanently prescribed one or more psychotropic drugs for treatment of symptoms, such as behavioral and psychological symptoms in dementia, depressive symptoms, anxiety, and insomnia. They therefore contribute to the risk of polypharmacy. Recently, deprescribing studies have been published in order to clarify if inadequate medications can be safely discontinued. This mini-review summarizes the study results and derives practical recommendations for routine use. METHOD: A literature search was carried out in PubMed for clinical studies on deprescribing in association with psychotropic substances. RESULTS: After removal of duplications, 12 heterogeneous clinical studies were identified and reduction of psychotropic substances could be successfully achieved in 8 studies. In four of these studies psychological, behavioral and functional endpoints were reported. Criteria for successful deprescribing of sedatives were in particular motivation, information and sufficient cooperation of the patients and for antipsychotic drugs in people with dementia, the sustainable establishment of nonpharmaceutical treatment strategies. Deprescribing was not attempted in cases of a history of severe chronic mental illness and in cases of severe behavioral symptoms in dementia. Evidence for antidepressants was not sufficient to extract practical recommendations. CONCLUSION: Safe deprescribing of antipsychotic drugs in patients with dementia is justified if non-pharmacological treatment options are sustainably implemented, and for sedative drugs in well-informed, highly motivated and cooperative patients.

Comparative short-term safety and efficacy of hypnotics: A quantitative risk-benefit analysis.

Several professional societies have provided recommendations for prescribing medications for insomnia. None has provided an integrative analysis that concurrently quantifies safety and efficacy (e.g., risk-benefit ratios). This represents an important gap for informing clinician decision-making. Accordingly, the aim of the present review is to provide such an analysis for five classes of sleep-promoting medications. Adverse event data values were extracted from the most recent FDA-approved package inserts and converted to an integer before being placebo-adjusted and standardized as a rate per 1000 (AEr). Efficacy data, pre-to-post self-reported data for active and placebo conditions were acquired from pivotal trials identified in "white papers" and systematic reviews/meta-analyses. Weighted effect sizes were calculated for subjective sleep latency, wake time after sleep onset and total sleep time, and then were averaged by medication class for each sleep continuity variable. Overall efficacy was represented by a single variable, SWT (sleep latency + wake time after sleep onset + total sleep time). Risk-benefit was represented using a simple ratio value. For safety, it was found that melatonin receptor agonists had the lowest adverse event rate (AEr = 43.1), and non-benzodiazepine benzodiazepine receptor agonists had the highest rate (AEr = 255.0). For efficacy, it was found that the pre-to-post placebo adjusted effect sizes were largest for benzodiazepines (effect size = 1.94) and smallest for melatonin receptor agonists (effect size = 0.109). For risk-benefit, histamine antagonist had the most favourable profile (risk-benefit = 69.5), while melatonin receptor agonist had the least favourable profile (risk-benefit = 395.7). Overall, the combined metric for risk-benefit suggests that treatment with a histamine antagonist is optimal and potentially represents the best first-line therapy for the medical management of insomnia.

Management of Phenibut Use Disorder and Withdrawal in a Geriatric Patient.

Phenibut is a misused substance which has shown an increase in use over the past decade. Marketed as a "dietary supplement," it is not approved in the United States for use and is not regulated by the Food and Drug Administration. The substance, however, is readily available for purchase through online markets. It has a similar drug profile as alcohol, gabapentin and benzodiazepines. Clinical effects of this drug include physiologic dependence, euphoria, anxiolysis, antispasticity, sedation, and possible nootropic properties. While there are emerging new cases of managing phenibut withdrawal, no cases currently feature phenibut addiction and withdrawal management in the geriatric population. Here we discuss such a case of phenibut addiction and withdrawal in a 68-year-old male who initially began misusing phenibut to alleviate anxiety and insomnia precipitated by worsening affective disorder, sedative, hypnotic, or anxiolytic use disorder, and alcohol use disorder.

Role of private prescriptions in the long-term use of benzodiazepines and Z-drugs: A patient-related follow-up study.

PURPOSE: To analyse (1) how often patients insured under the statutory health insurance (SHI) scheme received repeated prescriptions for benzodiazepines or Z-drugs as private prescriptions and (2) how often doctors switched from SHI prescriptions to private prescriptions and vice versa when issuing repeat prescriptions. METHODS: On basis of anonymized prescriptions from 874 ambulatory practices in Germany, we analysed the percentage of private prescriptions for Z-drugs, benzodiazepines/anxiolytics, and benzodiazepines/hypnotics and sedatives over 6 years (2014 to 2020). RESULTS: Of 2 200 446 prescriptions for a benzodiazepine or Z-drug, 38% were private prescriptions. In case of Z-drugs, the rate of private prescriptions was 44.1% for single prescriptions and 48.9% for refills. The difference was smaller for anxiolytics (23.3% vs. 26.0%) and, for benzodiazepine/hypnotics and sedatives, the proportion of private prescriptions for refills was even lower than for single prescriptions. In case of Z-drugs, the proportion of private prescriptions was, on average, 42.7% for the first prescription of a series of repeat prescriptions and 49.6% for the tenth prescription. The increase was smaller for anxiolytics and negligible for benzodiazepine/hypnotics and sedatives. Doctors stayed with their initial decision in more than three quarters of repeat prescriptions, be it a SHI or private prescription. CONCLUSION: While we observed a large number of private prescriptions for benzodiazepines and Z-drugs, the proportion was only slightly higher for refills than for single prescriptions. Doctors do not seem to issue private prescriptions as a strategy to mask especially long-term use of these substances.

Is anticholinergic and sedative drug burden associated with postdischarge institutionalization in community-dwelling older patients acutely admitted to hospital? A Norwegian registry-based study.

PURPOSE: Investigate the association between anticholinergic (AC) and sedative (SED) drug burden before hospitalization and postdischarge institutionalization (PDI) in community-dwelling older patients acutely admitted to hospital. METHODS: A cross-sectional study using data from the Norwegian Patient Registry and the Norwegian Prescription Database. We studied acutely hospitalized community-dwelling patients ≥70 years during 2013 (N = 86 509). Patients acutely admitted to geriatric wards underwent subgroup analyses (n = 1715). We calculated drug burden by the Drug Burden Index (DBI), use of AC/SED drugs, and the number of AC/SED drugs. Piecewise linearity of DBI versus PDI and a knot point (DBI = 2.45) was identified. Statistical analyses included an adjusted multivariable logistic regression model. RESULTS: In the total population, 45.4% were exposed to at least one AC/SED drug, compared to 52.5% in the geriatric subgroup. AC/SED drugs were significantly associated with PDI. The DBI with odds ratios (ORs) of 1.11 (95% CI 1.07-1.15) for DBI < 2.45 and 1.08 (95% CI 1.04-1.13) for DBI ≥ 2.45. The number of AC/SED drugs with OR of 1.07 (95% CI 1.05-1.09). The AC component of DBI with OR 1.23 and the number of AC drugs with OR 1.13. In the subgroup, ORs were closer to 1 for AC drugs. CONCLUSIONS: The use of AC/SED drugs was highly prevalent in older patients before acute hospital admissions, and significantly associated with PDI. The number, or just using AC/SED drugs, gave similar associations with PDI compared to applying the DBI. Using AC drugs showed higher sensitivity, indicating that to reduce the risk of PDI, a clinical approach could be to reduce the number of AC drugs.

Efficacy and safety of hydroxyzine for sleep in adults: Systematic review.

OBJECTIVE: The purpose of this systematic review is to assess the efficacy and safety of hydroxyzine for insomnia in adults. METHODS: A comprehensive literature search of PubMed, Embase, and CENTRAL databases was conducted to identify relevant published studies through October 2022 using the search terms: hydroxyzine and sleep, insomnia, sleep disorder or sleep initiation and maintenance disorders. Studies identified for review included prospective, interventional designs or cohort trials that reported impact of hydroxyzine on sleep in adults. Animal studies, case reports, non-English articles, letters to the editor, case studies, and conference abstracts were excluded. Data were extracted using a standardized systematic process. RESULTS: Five articles were identified for inclusion, including 1 open-label and 4 randomized controlled trials, evaluating a total of 207 patients receiving hydroxyzine 25 mg, 50 mg, or 100 mg at bedtime. Mixed efficacy was demonstrated in the sleep measures of sleep onset, sleep maintenance, and sleep quality. The most common adverse drug effect was dry mouth, although 4 of the 5 studies did not report safety outcomes. CONCLUSIONS: The studies in this review suggest hydroxyzine could be considered as a short-term treatment option for adults with insomnia for whom previous therapy was ineffective, not tolerated, or contraindicated. Additional long-term studies with an active comparator are needed to further establish its role in insomnia treatment.

"It's pretty much flying blind in the home care setting": A qualitative study on the influence of home care specific circumstances on sedation in specialist palliative home care.

BACKGROUND: Existing data on sedation at the end of life indicate challenges in the home care setting, leading to deviations from guidelines or non-provision of sedation. AIM: As part of the "SedPall" study, we aimed to explore circumstances in specialist palliative home care, which influence the practice of sedation. DESIGN: Semi-structured qualitative interviews (n = 59) and two focus groups (n = 4, n = 5). Recruitment took place via contact persons. We thematically analyzed the transcripts with the Framework Approach, using MAXQDA 2018.2. SETTING/PARTICIPANTS: Physicians, nurses, and other members of the multiprofessional team from 10 palliative care units and seven home care teams. RESULTS: Participants reported home care specific circumstances that can be categorized into three interrelated topics. (1) Lack of 24/7 on-site availability, (2) active involvement of the family, (3) challenges regarding teamwork and multidisciplinarity. Participants drew different conclusions from the reported circumstances regarding the feasibility of different types of sedation at home: While some reported to generally use all types of sedation, others stated that some types of sedation are not feasible in home care, for example deep sedation until death. Most participants questioned the applicability of existing sedation guidelines in the home care setting. CONCLUSION: Our data indicate that sedation practices might currently follow the healthcare professional's attitude or service policy rather than the patient's need. To avoid hospital admission in manageable cases and ensure that home care specific best practice standards are met, existing guideline recommendations have to be adapted and supplemented by additional supporting measures specific for the home care setting.

Raw Pinelliae Rhizoma: examination of sedative and hypnotic effects in mice and chemical analysis.

PURPOSE: Raw "Pinelliae Rhizoma" (RPR) is widely used in Chinese clinics to treat insomnia. This study investigated its underlying sedative and hypnotic mechanisms and main active components. METHODS: A locomotor activity test was used to evaluate the sedative effects of RPR at three dosages (0.2 g/mL, 0.4 g/mL, and 0.8 g/mL) in mice. Polysomnography was used to assess its ability to improve sleep. Ultra-performance liquid chromatography/time of flight/mass spectrometry (UPLC-TOF-MS) analysis was used to identify the potential active components of RPR. RESULTS: Mice in the RPR groups were less active than mice in the vehicle group; this difference was greatest in the 0.8 g/mL RPR group. Compared with the vehicle, 0.8 g/mL RPR increased the duration of rapid eye movement (REM) sleep in the dark phase. In addition, the duration of wakefulness in the 0.8 g/mL RPR group decreased with increasing durations of nonrapid eye movement (NREM) and REM sleep. Compared with diazepam, 0.8 g/mL RPR increased REM sleep duration in both the light and dark phases and increased the number of transitions both from NREM sleep to REM sleep and from REM sleep to wakefulness. A total of 33 RPR constituents, including 15 alkaloids, were identified. CONCLUSION: The results preliminarily indicated that RPR exerts sedative and hypnotic effects in mice, mainly leading to improvements in REM sleep. These effects are possibly due to the alkaloid constituents of RPR.

Psychotropic consumption before and during COVID-19 in Asturias, Spain.

BACKGROUND: Spain as multiple other countries has been experiencing an increasing and sustained trend in the use of psychotropic medications since the mid 90s. Recent studies show public health measures implemented to control SARS-Cov2, such as mobility restrictions and the shutdown of nonessential activities increased mental suffering, even contributing to a higher number of anxiety, depression and insomnia disorders that could lead to an increase in the consumption of psychotropics. The aims were: 1) Evaluate the temporal trend in psychotropic consumption by pharmacological subgroup, sex, and age group 2) Estimate the effect of the COVID-19 pandemic in the use of psychotropic drugs. METHODS: We conducted a retrospective observational study, retrieving all prescriptions of anxiolytics, hypnotics and sedatives, and antidepressants dispensed in pharmacies of Asturias (Northern Spain) for Primary Care patients for the period 2018-2021. We presented the data expressed in Daily Defined Doses (DDDs) for 1000 persons/day (DHD). To estimate changes in DHDs by year and age group we conducted two multiple linear regressions (one for males and one for females) for every pharmacological subgroup studied. Changes were considered statistically significant when the regression coefficient was p < 0.05. We used the Software R 4.1.0. RESULTS: For the studied period, the highest DHDs are for antidepressants, although all of the subgroups experienced an increase in consumption rates. Women consumed more psychotropic drugs than men. In 2021, 372 out of every 1000 women were taking daily 1 DDD of these drugs versus 184 out of every 1000 men. Consumption rates for all psychotropic drugs progressively increases with age. Conversely, the biggest increases in consumption were among the youngest age groups (0-14 and 15-29 years) for women, while for men there is more variability. The regression models suggest an upward trend in psychotropic consumption during all the period, especially remarkable from 2020, for both genders and all age groups. CONCLUSIONS: - The consumption of psychotropic drugs has gradually increased over the last 4 years, with a significant boost starting in 2020 for both sexes, matching the start of the SARS-COV2 pandemic and the implementation of strict Public Health measures to contain it. - The increase observed on children and adolescents is a matter of concern.

Dexmedetomidine versus haloperidol for sedation of non-intubated patients with hyperactive delirium during the night in a high dependency unit: study protocol for an open-label, parallel-group, randomized controlled trial (DEX-HD trial).

BACKGROUND: Delirium is common in critically ill patients. Haloperidol has long been used for the treatment of delirium. Dexmedetomidine has recently been used to treat delirium among intubated critically ill patients. However, the efficacy of dexmedetomidine for delirium in non-intubated critically ill patients remains unknown. We hypothesize that dexmedetomidine is superior to haloperidol for sedation of patients with hyperactive delirium, and would reduce the prevalence of delirium among non-intubated patients after administration. We will conduct a randomized controlled trial to compare dexmedetomidine and haloperidol for the treatment of nocturnal hyperactive delirium in non-intubated patients in high dependency units (HDUs). METHODS: This is an open-label, parallel-group, randomized controlled trial to compare the efficacy and safety of dexmedetomidine and haloperidol for nocturnal hyperactive delirium in non-intubated patients at two HDUs of a tertiary hospital. We will recruit consecutive non-intubated patients who are admitted to the HDU from the emergency room, and allocate them in a 1:1 ratio to the dexmedetomidine or haloperidol group in advance. The allocated investigational drug will be administered only when participants develop hyperactive delirium (Richmond Agitation-Sedation Scale [RASS] score ≥1 and a positive score on the Confusion Assessment Method for the ICU between 19:00 and 6:00 the next day) during the night at an HDU. Dexmedetomidine is administered continuously, while haloperidol is administered intermittently. The primary outcome is the proportion of participants who achieve the targeted sedation level (RASS score of between -3 and 0) 2h after the administration of the investigational drug. Secondary outcomes include the sedation level and prevalence of delirium on the day following the administration of the investigational drugs, and safety. We plan to enroll 100 participants who develop nocturnal hyperactive delirium and receive one of the two investigational drugs. DISCUSSION: This is the first randomized controlled trial to compare the efficacy and safety of dexmedetomidine and haloperidol for sedation of non-intubated critically ill patients with hyperactive delirium in HDUs. The results of this study may confirm whether dexmedetomidine could be another option to sedate patients with hyperactive delirium. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCT1051220015, registered on 21 April 2022.

Potential pharmacological confounders in the setting of death determined by neurologic criteria: a narrative review.

Guidelines for the determination of death by neurologic criteria (DNC) require an absence of confounding factors if clinical examination alone is to be used. Drugs that depress the central nervous system suppress neurologic responses and spontaneous breathing and must be excluded or reversed prior to proceeding. If these confounding factors cannot be eliminated, ancillary testing is required. These drugs may be present after being administered as part of the treatment of critically ill patients. While measurement of serum drug concentrations can help guide the timing of assessments for DNC, they are not always available or feasible. In this article, we review sedative and opioid drugs that may confound DNC, along with pharmacokinetic factors that govern the duration of drug action. Pharmacokinetic parameters including a context-sensitive half-life of sedatives and opioids are highly variable in critically ill patients because of the multitude of clinical variables and conditions that can affect drug distribution and clearance. Patient-, disease-, and treatment-related factors that influence the distribution and clearance of these drugs are discussed including end organ function, age, obesity, hyperdynamic states, augmented renal clearance, fluid balance, hypothermia, and the role of prolonged drug infusions in critically ill patients. In these contexts, it is often difficult to predict how long after drug discontinuation the confounding effects will take to dissipate. We propose a conservative framework for evaluating when or if DNC can be determined by clinical criteria alone. When pharmacologic confounders cannot be reversed, or doing so is not feasible, ancillary testing to confirm the absence of brain blood flow should be obtained.

RéSUMé: Les lignes directrices pour la détermination du décès selon des critères neurologiques (DCN) exigent une absence de facteurs confondants si l'examen clinique seul doit être utilisé. Les médicaments qui dépriment le système nerveux central suppriment les réponses neurologiques et la respiration spontanée et doivent être exclus ou neutralisés avant de procéder. Si ces facteurs confondants ne peuvent être éliminés, un examen auxiliaire est nécessaire. Ces médicaments peuvent être présents après avoir été administrés dans le cadre du traitement de patients en état critique. Bien que la mesure des concentrations sériques de médicaments puisse guider l'horaire des évaluations pour un DCN, ces mesures ne sont pas toujours disponibles ou réalisables. Dans cet article, nous passons en revue les médicaments sédatifs et opioïdes qui peuvent confondre un DCN, ainsi que les facteurs pharmacocinétiques qui régissent la durée d'action de ces médicaments. Les paramètres pharmacocinétiques, y compris une demi-vie des sédatifs et des opioïdes sensible au contexte, sont très variables chez les patients gravement malades en raison de la multitude de variables cliniques et de conditions qui peuvent affecter la diffusion et l'élimination des médicaments. Les facteurs liés au patient, à la maladie et au traitement qui influencent la diffusion et l'élimination de ces médicaments sont discutés, notamment la fonction des organes cibles, l'âge, l'obésité, les états hyperdynamiques, l'augmentation de la clairance rénale, l'équilibre liquidien, l'hypothermie et le rôle des perfusions prolongées de médicaments chez les patients gravement malades. Dans ces contextes, il est souvent difficile de prédire combien de temps après l'arrêt du médicament les effets confusionnels prendront pour se dissiper. Nous proposons un cadre conservateur pour évaluer quand ou si un DCN peut être déterminé selon des critères cliniques uniquement. Lorsque les facteurs confondants pharmacologiques ne peuvent pas être neutralisés, ou que cela n'est pas possible, un examen auxiliaire pour confirmer l'absence de circulation sanguine cérébrale doit être réalisé.

Aerosol generation during paediatric procedural sedation with continuous-flow nitrous oxide suggests a low risk of airborne viral transmission to health-care workers.

AIM: Inhaled nitrous oxide is a common form of procedural sedation in paediatric care. During the COVID-19 pandemic, concerns about potential aerosol generation and associated viral transmission to health-care workers have led to controversy regarding its use. We aimed to measure the degree of aerosol generation during continuous flow nitrous oxide sedation to inform future guidelines. METHODS: Aerosol numbers in the respirable range were measured using a particle counter during 30 procedures undertaken in children under nitrous oxide sedation in the Emergency Department. RESULTS: Changes from baseline measurements were greatest in particles in the 0.3 µm range. The mean increase from baseline in 0.3 µm particles per cubic metre was 18 022 (95% confidence interval (CI) 5949-30 096) after the child entered the room, and 2931 (95% CI -4407 to 10 269) during nitrous oxide administration. CONCLUSION: Variation of respirable particle numbers from baseline levels was no greater during nitrous oxide administration than for breathing and talking asymptomatic children. These results suggest the additional risk of airborne viral transmission to staff during inhaled nitrous oxide sedation is low.