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

BACKGROUND: Dexmedetomidine and midazolam are commonly used sedatives in children. We conducted a systematic review and meta-analysis to compare the safety and effectiveness of sedation provided by dexmedetomidine combined with midazolam versus other sedatives including chloral hydrate, midazolam and other sedatives in pediatric sedation.
METHODS: The Embase, Web of Science, Cochrane Library, and PubMed databases, and Clinicaltrials.gov register of controlled trials were searched from inception to June 2022. All randomized controlled trials used dexmedetomidine-midazolam in pediatric sedation were enrolled. The articles search, data extraction, and quality assessment of included studies were performed independently by two researchers. The success rate of sedation was considered as the primary outcome. The secondary outcomes included onset time of sedation, recovery time of sedation and occurrence of adverse events.
RESULTS: A total of 522 studies were screened and 6 RCTs were identified; 859 patients were analyzed. The administration of dexmedetomidine combined with midazolam was associated with a higher sedation success rate and a lower incidence of nausea and vomiting in computed tomography, magnetic resonance imaging, Auditory Brainstem Response test or fiberoptic bronchoscopy examinations than the other sedatives did (OR = 2.92; 95% CI: 1.39-6.13, P = 0.005, I2 = 51%; OR = 0.23, 95% CI: 0.07-0.68, P = 0.008, I2 = 0%, respectively). Two groups did not differ significantly in recovery time and the occurrence of adverse reactions (WMD = - 0.27, 95% CI: - 0.93 to - 0.39, P = 0.42; OR 0.70; 95% CI: 0.48-1.02, P = 0.06, I2 = 45%. respectively). However, the results of the subgroup analysis of ASA I-II children showed a quicker onset time in dexmedetomidine-midazolam group than the other sedatives (WMD=-3.08; 95% CI: -4.66 to - 1.49, P = 0.0001, I2 = 30%).
CONCLUSIONS: This meta-analysis showed that compared with the control group, dexmedetomidine combined with midazolam group provided higher sedation success rates and caused a lower incidence of nausea and vomiting in completing examinations, indicating a prospective outpatient clinical application for procedural sedation.

BACKGROUND: Dexmedetomidine (Dex), midazolam, and propofol are three distinct sedatives characterized by varying pharmacological properties. Previous literature has indicated the positive impact of each of these sedatives on ICU patients. However, there is a scarcity of clinical evidence comparing the efficacy of Dex, midazolam, and propofol in reducing mortality among people with epilepsy (PWE). This study aimed to assess the impact of Dex, midazolam, and propofol on the survival of PWE.
METHODS: The data were retrospectively retrieved from the Medical Information Mart for Intensive Care (MIMIC)-IV database (version 2.0). PWE were categorized into Dex, midazolam, and propofol groups based on the intravenously administered sedatives. PWE without standard drug therapy were included in the control group. Comparative analyses were performed on the data among the groups.
RESULTS: The Dex group exhibited a significantly lower proportion of in-hospital deaths and a markedly higher in-hospital survival time compared to the midazolam and propofol groups (p < 0.01) after propensity score matching. Kaplan-Meier curves demonstrated a significant improvement in survival rates for the Dex group compared to the control group (p = 0.025). Analysis of Variance (ANOVA) revealed no significant differences in survival rates among the Dex, midazolam, and propofol groups (F = 1.949, p = 0.143). The nomogram indicated that compared to midazolam and propofol groups, Dex was more effective in improving the survival rate of PWE.
CONCLUSIONS: Dex might improve the survival rate of PWE in the ICU compared to no standard drug intervention. However, Dex did not exhibit superiority in improving survival rates compared to midazolam and propofol.

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

BACKGROUND: The aims of this study were to investigate the independent risk factors associated with iatrogenic withdrawal syndrome in pediatric intensive care units (PICUs) and to establish receiver operator characteristic (ROC) curve to facilitate the diagnosis of iatrogenic withdrawal syndrome in clinical settings.
METHODS: Pediatric patients who received analgesic and sedative medication at a tertiary hospital in the southern Zhejiang region of China between January 2016 and December 2022 were selected for the study. Clinical case data were retrospectively analyzed to gather information including age, gender, weight, total dose of analgesic and sedative medication, total treatment duration, average maintenance dose, and other relevant parameters. Medically induced withdrawal symptom scores were assessed using the Sophia Observation Scale for Withdrawal Symptoms (SOS). Univariate and multivariate logistic regression analyses were conducted on the above indicators to identify the risk factors for iatrogenic withdrawal, and an ROC curve was constructed.
RESULTS: The study encompassed a total of 104 pediatric patients, comprising 47 patients in the SOS score ≥4 group and 57 patients in the SOS score ≤3 group. The incidence of iatrogenic withdrawal was 45.19%. Univariate analysis identified cumulative total dose of fentanyl, average daily dose of fentanyl, average daily dose of midazolam, and patient weight (p < 0.05) as factors associated with iatrogenic withdrawal syndrome. The logistic multiple regression analysis revealed that the average daily dose of fentanyl was an independent risk factor for the occurrence of iatrogenic withdrawal syndrome in critically ill children (p < 0.05). ROC curve analysis indicated an area under the curve of 0.711 (95% CI: 0.610-0.811) with sensitivity and specificity of 73.7% and 61.7%, respectively.
CONCLUSIONS: The average daily maintenance dose of fentanyl holds significant clinical value in diagnosing and evaluating the prognosis of iatrogenic withdrawal syndrome and can provide a scientific foundation for enhancing sedative and analgesic management in clinical practice.

BACKGROUND: Colonoscopy is a commonly performed gastroenterological procedure in patients associated with anxiety and pain. Various approaches have been used to provide sedation and analgesia during colonoscopy, including patient-controlled analgesia and sedation (PCAS). This study aims to evaluate the feasibility and efficiency of PCAS administered with propofol and remifentanil for colonoscopy.
METHODS: This randomized controlled trial was performed in an authorized and approved endoscopy center. A total of 80 outpatients were recruited for the colonoscopy studies. Patients were randomly allocated into PCAS and total intravenous anesthesia (TIVA) groups. In the PCAS group, the dose of 0.1 ml/kg/min of the mixture was injected after an initial bolus of 3 ml mixture (1 ml containing 3 mg of propofol and 10 μg of remifentanil). Each 1 ml of bolus was delivered with a lockout time of 1 min. In the TIVA group, patients were administered fentanyl 1 μg/kg, midazolam 0.02 mg/kg, and propofol (dosage titrated). Cardiorespiratory parameters and auditory evoked response index were continuously monitored during the procedure. The recovery from anesthesia was assessed using the Aldrete scale and the Observer\'s Assessment of Alertness/Sedation Scale. The Visual Analogue Scale was used to assess the satisfaction of patients and endoscopists.
RESULTS: No statistical differences were observed in the Visual Analogue Scale scores of the patients (9.58 vs 9.50) and the endoscopist (9.43 vs 9.30). A significant decline in the mean arterial blood pressure, heart rate, and auditory evoked response index parameters was recorded in the TIVA group (P < 0.05). The recovery time was significantly shorter in the PCAS group than in the TIVA group (P = 0.00).
CONCLUSIONS: The combination of remifentanil and propofol could provide sufficient analgesia, better hemodynamic stability, lighter sedation, and faster recovery in the PCAS group of patients compared with the TIVA group.

BACKGROUND: Proper sedation of patients, particularly elderly individuals, who are more susceptible to sedation-related complications, is of significant importance in endoscopic retrograde cholangiopancreatography (ERCP). This study aims to assess the safety and efficacy of a low-dose combination of midazolam, alfentanil, and propofol for deep sedation in elderly patients undergoing ERCP, compared to a group of middle-aged patients.
METHODS: The medical records of 610 patients with common bile duct stones who underwent elective ERCP under deep sedation with a three-drug regimen, including midazolam, alfentanil, and propofol at Shandong Provincial Third Hospital from January 2023 to September 2023 were retrospectively reviewed in this study. Patients were categorized into three groups: middle-aged (50-64 years, n = 202), elderly (65-79 years, n = 216), and very elderly (≥ 80 years, n = 192). Intraoperative vital signs and complications were compared among these groups.
RESULTS: The three groups showed no significant difference in terms of intraoperative variation of systolic blood pressure (P = 0.291), diastolic blood pressure (P = 0.737), heart rate (P = 0.107), peripheral oxygen saturation (P = 0.188), bispectral index (P = 0.158), and the occurrence of sedation-related adverse events including hypotension (P = 0.170) and hypoxemia (P = 0.423).
CONCLUSIONS: The results suggest that a low-dose three-drug regimen consisting of midazolam, alfentanil, and propofol seems safe and effective for deep sedation of elderly and very elderly patients undergoing ERCP procedures. However, further studies are required to verify these findings and clarify the benefits and risks of this method.

This study aims to explore and characterize the role of pediatric sedation via rectal route. A pediatric physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) model of midazolam gel was built and validated to support dose selection for pediatric clinical trials. Before developing the rectal PBPK model, an intravenous PBPK model was developed to determine drug disposition, specifically by describing the ontogeny model of the metabolic enzyme. Pediatric rectal absorption was developed based on the rectal PBPK model of adults. The improved Weibull function with permeability, surface area, and fluid volume parameters was used to extrapolate pediatric rectal absorption. A logistic regression model was used to characterize the relationship between the free concentrations of midazolam and the probability of sedation. All models successfully described the PK profiles with absolute average fold error (AAFE) < 2, especially our intravenous PBPK model that extended the predicted age to preterm. The simulation results of the PD model showed that when the free concentrations of midazolam ranged from 3.9 to 18.4 ng/mL, the probability of \"Sedation\" was greater than that of \"Not-sedation\" states. Combined with the rectal PBPK model, the recommended sedation doses were in the ranges of 0.44-2.08 mg/kg for children aged 2-3 years, 0.35-1.65 mg/kg for children aged 4-7 years, 0.24-1.27 mg/kg for children aged 8-12 years, and 0.20-1.10 mg/kg for adolescents aged 13-18 years. Overall, this model mechanistically quantified drug disposition and effect of midazolam gel in the pediatric population, accurately predicted the observed clinical data, and simulated the drug exposure for sedation that will inform dose selection for following pediatric clinical trials.

BACKGROUND: The exact median effective dose (ED50) of intranasal dexmedetomidine combined with oral midazolam sedation for magnetic resonance imaging (MRI) examination in children remains unknow and the aim of this study was to determine the ED50 of their combination.
METHODS: This is a prospective dose-finding study. A total of 53 children aged from 2 months to 6 years scheduled for MRI examination from February 2023 to April 2023 were randomly divided into group D (to determine the ED50 of intranasal dexmedetomidine) and group M (to determine the ED50 of oral midazolam). The dosage of dexmedetomidine and midazolam was adjusted according to the modified Dixon\'s up-and-down method, and the ED50 was calculated with a probit regression approach.
RESULTS: The ED50 of intranasal dexmedetomidine when combined with 0.5 mg∙kg- 1 oral midazolam was 0.39 µg∙kg- 1 [95% confidence interval (CI) 0.30 to 0.46 µg∙kg- 1] while the ED50 of oral midazolam was 0.17 mg∙kg- 1 (95% CI 0.01 to 0.29 mg∙kg- 1) when combined with 1 µg∙kg- 1 intranasal dexmedetomidine. The sedation onset time of children with successful sedation in group D was longer than in group M (30.0[25.0, 38.0]vs 19.5[15.0, 35.0] min, P < 0.05). No other adverse effects were observed in the day and 24 h after medication except one dysphoria.
CONCLUSIONS: This drug combination sedation regimen appears suitable for children scheduled for MRI examinations, offering a more precise approach to guide the clinical use of sedative drugs in children.
BACKGROUND: Chinese Clinical Trial Registry, identifier: ChiCTR2300068611(24/02/2023).

BACKGROUND: To date, there is no standardized practice for the use of pharmacological sedatives during flexible bronchoscopy, particularly for elderly patients. This exploratory study aimed to assess the efficacy and safety of remimazolam at a single induced dose for deep sedation in elderly patients undergoing diagnostic flexible bronchoscopy (DFB), and compare with midazolam, a commonly used sedative.
METHODS: A total of 100 elderly patients (age range 65-80 yr; American Society of Anesthesiologists Physical Status I-III) undergoing DFB were randomly allocated into 2 groups according to the sedatives used for induction: the remimazolam group and the midazolam group. Sedation induction was initiated by an intravenous bolus of remimazolam (0.135 mg/kg) or midazolam (0.045 mg/kg), respectively, both groups were combined with a high-dose of alfentanil (18 µg/kg), and supplemented with high-flow nasal cannula (HFNC) oxygen supply at a flow rate of 45 L/min. If the target depth of sedation was not achieved, propofol would be titrated as a rescue. The primary outcome was the success rate of sedation at a single induced dose to achieve target depth (Ramsay sedation score [RSS] = 4) during induction, intraoperative changes in vital signs, postoperative follow-up situation and incidence of post-bronchoscopy adverse events were evaluated as secondary outcomes.
RESULTS: The success rate of sedation in the remimazolam group was significantly higher than that in the midazolam group (65.2% vs 39.6%, P = .013), while the incidence of extra sleep within 6 hours after procedure was lower in the remimazolam group as compared to the midazolam group (10.9% vs 31.3%, P = .016). No statistically significant differences were observed between the 2 groups regarding hemodynamic fluctuations, incidence of hypoxemia, and cough response during the procedure, as well as postoperative recall, willingness to undergo reexamination, and other post-bronchoscopy adverse events.
CONCLUSIONS: Bolus administration of remimazolam offers advantages over midazolam for deep sedation in elderly patients undergoing DFB, in terms of a higher success rate of sedation and a lower incidence of extra sleep within 6 hours after procedure, though the safety profiles of both groups were favorable.