This prospective, blinded, randomized crossover study aimed to assess the anesthetic effects of the combination of 30 mg/kg ketamine and 2 mg/kg midazolam via intranasal (IN) or intramuscular (IM) routes in twelve domestic chickens. Physiological parameters (respiratory rate - RR, heart rate - HR, and cloacal temperature -Tºcloacal) were monitored throughout the experiment, along with recovery time and sedation level (S0: awake, no recumbency, responsive to stimuli; S1: blinking eyes, recumbency, relaxed, response to stimulus, mild movement; S2: open eyes, recumbency, relaxed, mild response to stimuli; S3: closed eyes, recumbency, relaxed, no movement). In the IM group, all birds reached S3, while in IN 5/12 reached S3, 4/12 reached at most S1, and 1/12 at most S2. IM administration showed higher sedation at 5, 10, 15, 20, 30, 35, 40, and 45 minutes (p<0.05). IN administration exhibited a shorter total recovery time (26.3±21.4 min vs. 92.9±33.4 min; p<0.001). No time, group, or time-group interaction effects were observed in HR and cloacal Tº, with a trend to a decrease in RR both groups (p<0.001). Increased incidences of vocalization and agitation was observed via IM (4/12 vs. 0/12; p=0.028), with no difference in salivation. Despite faster recovery with less agitation and vocalization, the ketamine and midazolam combination via IN provided less consistent sedation compared to the IM route in chickens.
Este estudo crossover randomizado objetivou avaliar os efeitos anestésicos da associação de 30 mg/kg de cetamina e 2 mg/kg de midazolam via intranasal (IN) ou intramuscular (IM) em doze galinhas. Além dos parâmetros fisiológicos (frequência respiratória – FR e cardíaca – FC e temperatura cloacal – Tºcloacal), registrou-se o tempo de recuperação e o grau de sedação ao longo do experimento (S0: acordada, sem decúbito, responsiva a estímulos; S1: olhos piscando, decúbito, relaxada, resposta a estímulo, movimentação leve; S2: olhos abertos, decúbito, relaxada, resposta leve a estímulos; S3: olhos fechados, decúbito, relaxada, sem movimentação. Pela via IM, todas as aves atingiram o grau S3, enquanto pela via IN 5/12 alcançaram S3, 4/12 atingiram no máximo S1 e 1/12 no máximo S2. A via IM apresentou maior sedação em 5, 10, 15, 20, 30, 35, 40 e 45 min (p<0,05). A via IN apresentou menor tempo total até recuperação (26,3±21,4 min vs. 92,9±33,4 min; p<0,001). Não foram observados efeitos de tempo, grupo e interação tempo-grupo na FC e na Tºcloacal com uma tendência de queda da FR nos dois grupos (p<0,001). Observou-se maior incidência de vocalização e agitação pela via IM (4/12 vs. 0/12; p=0,028), não havendo diferença para sialorreia. Apesar da recuperação mais rápida e com menos agitação e vocalização, a associação cetamina e midazolam via IN levou a uma sedação menos consistente que a via IM em galinhas.

This report evaluates the effects of chlordiazepoxide, a benzodiazepine commonly prescribed to manage anxiety-related disorders in adolescent/pediatric populations, on elevated plus maze (EPM) performance in juvenile mice. This approach was taken because chlordiazepoxide produces anxiolytic-like effects in multiple models in adult rodents, however, less is known about the behavioral effects of this benzodiazepine in juveniles. Thus, we administered a single intraperitoneal injection of chlordiazepoxide (0, 5, or 10 mg/kg) to postnatal day 35 male C57BL/6 mice. Thirty minutes later, mice were allowed to explore the EPM for 5-min. We found that chlordiazepoxide-treated mice (5 and 10 mg/kg) spent more time exploring the open arms of the EPM. No differences in velocity (cm/s) or distance traveled (cm) were observed between the groups. These results indicate that chlordiazepoxide induces anxiolytic-related behavior in adolescent male mice.

OBJECTIVE: Exposure to critical illness and intensive care may lead to long-term psychologic and physical impairments. To what extent ICU survivors become prolonged users of benzodiazepines after exposure to critical care is not fully explored. This study aimed to describe the extent of onset of prolonged high-potency benzodiazepine use among ICU survivors not using these drugs before admission, identify factors associated with this use, and analyze whether such usage is associated with increased mortality.
METHODS: Retrospective cohort study.
METHODS: Sweden, including all registered ICU admissions between 2010 and 2017.
METHODS: ICU patients surviving for at least 3 months, not using high-potency benzodiazepine before admission, were eligible for inclusion.
METHODS: Admission to intensive care.
RESULTS: A total of 237,904 patients were screened and 137,647 were included. Of these 5338 (3.9%) became prolonged users of high-potency benzodiazepines after ICU discharge. A peak in high-potency benzodiazepine prescriptions was observed during the first 3 months, followed by sustained usage throughout the follow-up period of 18 months. Prolonged usage was associated with older age, female sex, and a history of both somatic and psychiatric comorbidities, including substance abuse. Additionally, a longer ICU stay, a high estimated mortality rate, and prior consumption of low-potency benzodiazepines were associated with prolonged use. The risk of death between 6 and 18 months post-ICU admission was significantly higher among high-potency benzodiazepine users, with an adjusted hazard ratio of 1.8 (95% CI, 1.7-2.0; p < 0.001). No differences were noted in causes of death between users and nonusers.
UNASSIGNED: Despite the lack of evidence supporting long-term treatment, prolonged usage of high-potency benzodiazepines 18 months following ICU care was notable and associated with an increased risk of death. Considering the substantial number of ICU admissions, prevention of benzodiazepine misuse may improve long-term outcomes following critical care.

OBJECTIVE: The use of benzodiazepines and Z-hypnotics during pregnancy has raised significant concerns in recent years. However, there are limited data that capture the prescription patterns and predisposing factors in use of these drugs, particularly among women who have been long-term users of benzodiazepines and Z-hypnotics before pregnancy.
METHODS: This population-based cohort study comprised 2 930 988 pregnancies between 2004 and 2018 in Taiwan. Women who were dispensed benzodiazepines or Z-hypnotics during pregnancy were identified and further stratified into groups based on their status before pregnancy: long-term users (with a supply of more than 180 days within a year), short-term users (with a supply of less than 180 days within a year), and nonusers. Trends in the use of benzodiazepines or Z-hypnotics and concomitant use with antidepressants or opioids were assessed. Logistic regression models were utilized to identify factors associated with use of these drugs during pregnancy, and interrupted time series analyses (ITSA) were employed to evaluate utilization patterns of these drugs across different pregnancy-related periods.
RESULTS: The overall prevalence of benzodiazepine and Z-hypnotic use was 3.5% during pregnancy. Among prepregnancy long-term users, an upward trend was observed. The concomitant use of antidepressants or opioids among exposed women increased threefold (from 8.6% to 23.1%) and sixfold (from 0.3% to 1.7%) from 2004 to 2018, respectively. Women with unhealthy lifestyle behaviors, such as alcohol abuse (OR 2.48; 95% CI, 2.02-3.03), drug abuse (OR 10.34; 95% CI, 8.46-12.64), and tobacco use (OR 2.19; 95% CI, 1.96-2.45), as well as those with psychiatric disorders like anxiety (OR 6.99; 95% CI, 6.77-7.22), insomnia (OR 15.99; 95% CI, 15.55-16.45), depression (OR 9.43; 95% CI, 9.07-9.80), and schizophrenia (OR 21.08; 95% CI, 18.76-23.69), and higher healthcare utilization, were more likely to use benzodiazepines or Z-hypnotics during pregnancy. ITSA revealed a sudden decrease in use of benzodiazepines and Z-hypnotics after recognition of pregnancy (level change -0.55 percentage point; 95% CI, -0.59 to -0.51). In contrast, exposures to benzodiazepines and Z-hypnotics increased significantly after delivery (level change 0.12 percentage point; 95% CI, 0.09 to 0.16).
CONCLUSIONS: In this cohort study, an increased trend of benzodiazepine and Z-hypnotic use during pregnancy among prepregnancy long-term users, as well as concomitant use with antidepressants or opioids were found. The findings have highlighted the existence of various risk factors associated with the use of these drugs during pregnancy. Utilization patterns varied across different stages of pregnancy, highlighting the need for prescription guidelines and educational services for women using these drugs during pregnancy.

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BACKGROUND: Obsessive-compulsive disorder (OCD) is marked by a high rate of treatment resistance. Patients are often left trialing medications within multiple drug classes with little response, causing heterogeneity to emerge in prescribing patterns. This analysis seeks to investigate the selection and dosing of the pharmacotherapy utilized, to portray an overview of prescribing trends in the United States.
METHODS: This retrospective, single center, review of electronic medical records investigated the pharmacotherapy utilization of patients with a primary diagnosis of OCD. Two hundred and ninety-five patients who received OCD treatment at an urban, academic medical center were included in the study. Patients were included in the review if they were at least eighteen years of age and were assigned a diagnosis of OCD according to DSM-5 criteria.
RESULTS: Psychotropic pharmacotherapy was integrated into the care of 93% of patients. Selective serotonin reuptake inhibitors were the most utilized medication class at 85% followed by benzodiazepines (47%) and second-generation antipsychotics (37%). Tricyclic antidepressants and first-generation antipsychotics were the two medication classes utilized the least at 13% and 2% respectively. Additionally, mood stabilizers and serotonin-norepinephrine reuptake inhibitors were utilized at rates of 8% and 16%, respectively.
CONCLUSIONS: Evidence-based treatment guidelines are being followed with varying augmentation strategies widely prevalent, thus displaying the heterogeneity in treating OCD. A high rate of benzodiazepine utilization highlights a practice trend with potential ties to clinical factors, such as the latency to treatment effect of other first-line pharmacotherapies. Future prospective studies are required to determine the cultural, pharmacoeconomic and pharmacogenomic factors that contribute to the variation in prescribing practices and whether these variations influence treatment outcomes.

UNASSIGNED: Healthcare providers may be utilizing central nervous system (CNS) depressants to reduce opioid use due to recent changes in public policy. Combination use of these agents with opioids increases the risk of respiratory depression and death. Healthcare expenditures by individuals using these drug combinations have not been previously quantified. We sought to characterize healthcare costs and expenditures associated with a population reporting concurrent CNS depressants and opioid use compared with nonopioid analgesics in the United States from 2009 to 2019.
UNASSIGNED: A serial cross-sectional design was used to compare the healthcare expenditures of adult Medical Expenditure Panel Survey respondents who were prescribed nonopioid analgesics, opioids only, opioids/benzodiazepines (BZD), opioids/BZD/skeletal muscle relaxants (SMR), or opioids/gabapentin (gaba) using pooled data from 2009 to 2019. Expenditure (cost and resource utilization) categories included inpatient, outpatient, office-based, and prescription medicine. Average marginal effects were used to compare survey-weighted annual costs and resource utilizations across the groups as compared to nonopioid analgesic respondents, adjusted for covariates.
UNASSIGNED: A weighted total of 34 241 838 individuals were identified. Most were opioid-only respondents (46.5%), followed by nonopioid analgesic (43.4%), opioid/BZD (5.3%), opioid-gaba (3.5%), and opioid/BZD/SMR respondents (1.3%). In comparison to the study groups with nonopioid analgesics, opioid-gaba users had the highest significant incremental cost difference among the different pairings (+$11 684, P < .001). Opioid-gaba, opioid/BZD, and opioid/BZD/SMR respondents had significantly higher inpatient, emergency department, and prescription drug costs and use compared to nonopioid analgesic respondents. Opioid-only respondents had higher outpatient and office-based costs and visits compared to nonopioid analgesic respondents.
UNASSIGNED: As healthcare providers seek to utilize fewer opioids for pain management, attention must be paid to ensuring safe and effective use of concurrent CNS depressants to mitigate high healthcare costs and burden.

BACKGROUND: Benzodiazepines and other sedative hypnotic drugs (BSHs) are frequently prescribed for sleep problems, but cause substantial adverse effects, particularly in older adults. Improving knowledge on barriers, facilitators and needs of primary care providers (PCPs) to BSH deprescribing could help reduce BSH use and thus negative effects.
METHODS: We conducted a mixed methods study (February-May 2023) including a survey, semi-structured interviews and focus groups with PCPs in Switzerland. We assessed barriers, facilitators and needs of PCPs to BSH deprescribing. Quantitative data were analyzed descriptively, qualitative data deductively and inductively using the Theoretical Domain Framework (TDF). Quantitative and qualitative data were integrated using meta-interferences.
RESULTS: The survey was completed by 126 PCPs (53% female) and 16 PCPs participated to a focus group or individual interview. The main barriers to BSH deprescribing included patient and PCP lack of knowledge on BSH effects and side effects, lack of PCP education on treatment of sleep problems and BSH deprescribing, patient lack of motivation, PCP lack of time, limited access to cognitive behavioral therapy for insomnia and absence of public dialogue on BSHs. Facilitators included informing on side effects to motivate patients to discontinue BSHs and start of deprescribing during a hospitalization. Main PCP needs were practical recommendations for pharmacological and non-pharmacological treatment of sleep problems and deprescribing schemes. Patient brochures were wished by 69% of PCPs. PCPs suggested the brochures to contain explanations about risks and benefits of BSHs, sleep hygiene and sleep physiology, alternative treatments, discontinuation process and tapering schemes.
CONCLUSIONS: The barriers and facilitators as well as PCP needs and opinions on patient material we identified can be used to develop PCP training and material on BSH deprescribing, which could help reduce the inappropriate use of BSHs for sleep problems.

UNASSIGNED: Pharmacological avoidance guidelines for preventing delirium have been suggested; however, there are limited pragmatic studies of these strategies. Early (<24 h) delirium can be observed in the postoperative care unit and is associated with an increased risk of subsequent delirium. We examined the effectiveness of an avoid delirium protocol (ADP) in older (>65 years) patients undergoing elective surgeries.
UNASSIGNED: The randomized controlled trial assessed an ADP developed using the American Geriatric Society\'s Clinical Practice Guidelines for Postoperative Delirium in Older Adults, on early (<24 h) incident or subsyndromal delirium. Delirium was assessed using the confusion assessment method before surgery, in the post-anesthesia care unit, and on postoperative day 1. The primary outcome of early delirium was the combined incidence of incident or subsyndromal delirium.
UNASSIGNED: Early delirium was identified in 24/235 patients (10.2%) with a risk ratio of 1.27 (95% CI 0.59-2.73, P = 0.667) for patients randomized to the ADP. In cases with protocol adherence and no benzodiazepine use, early delirium was present in 10/ 73 (13.7%) compared to 14/148 (9.5%) in non-adherent cases [risk ratio 1.45 (95% CI 0.57-3.10, P = 0.362)]. Lower American Society of Anesthesiologists physical class [odds ratio 3.31 (95% CI 1.35-8.92, P = 0.008)] and an inpatient admission [odds ratio 2.67 (95% CI 1.55-4.87, P = 0.0002)] were associated with early delirium.
UNASSIGNED: Our findings suggest that pharmacological avoidance protocols limiting or avoiding the use of specific classes of medications are not effective in reducing early incident or subsyndromal delirium in older patients undergoing elective surgery.

BACKGROUND: Seizure clusters, prolonged seizures, and status epilepticus are life-threatening neurological emergencies leading to irreversible neuronal damage. Benzodiazepines are current evidence-based rescue therapy options; however, recent investigations indicated the prescription of mainly unsuitable benzodiazepines and inappropriate use of rescue medication.
OBJECTIVE: To examine current use, satisfaction, and adverse events concerning rescue medication in patients with epilepsy in Germany.
METHODS: The study was conducted at epilepsy centres in Frankfurt am Main, Greifswald, Marburg, and Münster between 10/2020 and 12/2020. Patients with an epilepsy diagnosis were assessed based on a questionnaire examining a 12-month period.
RESULTS: In total, 486 patients (mean age: 40.5, range 18-83, 58.2 % female) participated in this study, of which 125 (25.7 %) reported the use of rescue medication. The most frequently prescribed rescue medications were lorazepam tablets (56.8 %, n = 71 out of 125), buccal midazolam (19.2 %, n = 24), and rectal diazepam (10.4 %, n = 13). Seizures continuing for over several minutes (43.2 %, n = 54), seizure clusters (28.0 %, n = 35), and epileptic auras (28.0 %, n = 35) were named as indications, while 28.0 % (n = 35) stated they administered the rescue medication for every seizure. Of those continuing to have seizures, 46.0 % did not receive rescue medication. On average, rescue medication prescription occurred 7.1 years (SD 12.7, range 0-66) after an epilepsy diagnosis.
CONCLUSIONS: Unsuitable oral benzodiazepines remain widely prescribed for epilepsy patients as rescue medication. Patients also reported inappropriate use of medication. A substantial proportion of patients who were not seizure-free did not receive rescue medication prescriptions. Offering each patient at risk for prolonged seizures or clusters of seizures an individual rescue treatment with instructions on using it may decrease mortality and morbidity and increase quality of life. .