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The optimal sedation strategy for gastrointestinal endoscopy remains debated. This study compared the efficacy and safety of remimazolam combined with etomidate versus propofol for procedural sedation during gastrointestinal endoscopy. This single-center, randomized controlled clinical trial was performed from March 2024 to April 2024. A total of 262 patients scheduled to undergo gastrointestinal endoscopy were randomly assigned to receive remimazolam-etomidate (RE) or remimazolam-propofol (RP). The primary outcome was the incidence of respiratory depression. Secondary outcomes included the results of sedation and recovery. The safety results mainly include the incidence of hypotension, bradycardia, tachycardia, painful injection and muscular tremor. Statistical analyses included t-tests, Mann-Whitney U tests, and χ² tests for group comparisons, with subgroup analyses and multivariable logistic regression to assess the robustness of primary outcome. Respiratory depression occurred in 20.0% (25/125) of RE patients versus 32.3% (40/124) of RP patients (OR=0.52; 95% CI = 0.29-0.93; p = 0.028). There was a statistically significant difference in the distribution of the number of airway interventions between the two groups (p = 0.043), with 18 patients (14.5%) in the RP group requiring three airway interventions and only seven patients (5.6%) in the RE group. Hypoxemia occurred in three patients (2.4%) in the RE group and in five patients (4.0%) in the RP group. Hypotension was observed in 23.2% of patients sedated with RE versus 36.3% of patients sedated with RP (p = 0.024). Remimazolam-etomidate demonstrated a superior safety profile, with reduced respiratory depression and hemodynamic instability compared to remimazolam-propofol, suggesting its potential as a safer alternative for gastrointestinal endoscopy sedation. This trial was prospectively registered at the Chinese Clinical Trial Registry (ChiCTR2400085904) prior to patient enrollment.

Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA A ) receptors to dampen neuronal activity in the brain 1 – 5 . However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA A receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA A receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain. Cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics and benzodiazepines reveal both common and distinct transmembrane binding sites, and show that the mechanisms of action of anaesthetics partially overlap with those of benzodiazepines.

The optimal sedation regime during endoscopy remains controversial, especially for elderly outpatients. In this study, we compared the efficacy and safety between remimazolam tosilate (RT) and etomidate-propofol (EP) in elderly outpatients undergoing colonoscopy. A total of 260 elderly outpatients undergoing sedative colonoscopy were randomized into two groups. Patients in the RT group received a 0.075-mg/kg maintenance dose of remimazolam following an initial dose of 0.15 mg/kg, whereas patients in the EP group (10 mL:20 mg etomidate plus 10 mL:100 mg propofol) received a 0.05-mL/kg maintenance dose following an initial dose of 0.1 mL/kg to maintain a Modified Observer's Assessment of Alertness/Sedation score of ≤3 during the procedure. The primary endpoint was the success of the procedure. Secondary endpoints included time metrics, hemodynamics, consumption of fentanyl, etomidate, propofol, and remimazolam, intraoperative body movement, patient and endoscopist satisfaction scores, supplemental dose of sedative and fentanyl, and incidence and severity of adverse events. The procedure success rate was 96.52% in the RT group and 100% in the EP group. The difference in procedure success rate between the RT and EP groups was -3.48% (95% confidence interval: -6.81%, -0.15%). Four patients in the RT group required rescue midazolam. Compared with patients in the RT group, the onset time of the EP group was significantly lower ( < 0.05), whereas time to fully alert ( = 0.001), ready for discharge ( = 0.001), and hospital discharge ( = 0.002) were all significantly higher in the EP group. However, there were no significant differences in procedure time ( = 0.846) or cecal intubation time ( = 0.320) between the two groups. Although the frequency of intraoperative body movement was higher in the RT group, the difference was not significant ( = 0.508). There were no significant differences in patients' demographic and baseline characteristics, supplemental doses of sedative and fentanyl, or patient and endoscopist satisfaction scores ( > 0.05). Muscular tremor and pain on injection were recorded more frequently in the EP group ( < 0.05). However, there were no significant differences in hypoxia, respiratory depression, or incidence of postoperative nausea and vomiting. The severity of adverse events was all mild (grade 1) across both groups. RT may have non-inferior efficacy and a higher safety profile than EP in elderly outpatients undergoing colonoscopy, which suggests that RT may be more suitable for elderly outpatients undergoing colonoscopy.

Critically ill patients often require emergency intubation. The use of etomidate as the sedative agent in this context has been challenged because it might cause a reversible adrenal insufficiency, potentially associated with increased in-hospital morbidity. We compared early and 28-day morbidity after a single dose of etomidate or ketamine used for emergency endotracheal intubation of critically ill patients. In this randomised, controlled, single-blind trial, 655 patients who needed sedation for emergency intubation were prospectively enrolled from 12 emergency medical services or emergency departments and 65 intensive care units in France. Patients were randomly assigned by a computerised random-number generator list to receive 0·3 mg/kg of etomidate (n=328) or 2 mg/kg of ketamine (n=327) for intubation. Only the emergency physician enrolling patients was aware of group assignment. The primary endpoint was the maximum score of the sequential organ failure assessment during the first 3 days in the intensive care unit. We excluded from the analysis patients who died before reaching the hospital or those discharged from the intensive care unit before 3 days (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00440102. 234 patients were analysed in the etomidate group and 235 in the ketamine group. The mean maximum SOFA score between the two groups did not differ significantly (10·3 [SD 3·7] for etomidate vs 9·6 [3·9] for ketamine; mean difference 0·7 [95% CI 0·0–1·4], p=0·056). Intubation conditions did not differ significantly between the two groups (median intubation difficulty score 1 [IQR 0–3] in both groups; p=0·70). The percentage of patients with adrenal insufficiency was significantly higher in the etomidate group than in the ketamine group (OR 6·7, 3·5–12·7). We recorded no serious adverse events with either study drug. Our results show that ketamine is a safe and valuable alternative to etomidate for endotracheal intubation in critically ill patients, and should be considered in those with sepsis. French Ministry of Health.

Background Cipepofol, a novel anesthetic agent, may offer advantages for older patients undergoing painless digestive endoscopy. This study evaluated the safety and efficacy of this approach compared to a combination of etomidate and propofol (EP). Methods In this single-center, double-blind, randomized, non-inferiority trial, 120 older patients(aged 65–90 years) undergoing painless gastroscopy or colonoscopy were randomized to receive either cipepofol (0.3–0.4 mg/kg; n  = 60) or EP (1:1 ratio, 0.15–0.2 mL/kg; n  = 60). Primary outcomes included sedation duration. Secondary outcomes assessed sedation success, recovery time, discharge readiness, adverse events, and hemodynamic stability. Results All patients achieved successful sedation (100%). Initial sedation duration was comparable between the cipepofol and EP groups (8.73 [5.10, 10.18] vs. 7.41 [5.35, 9.09] minutes; p  = 0.165). Recovery times were similar (5.49 [3.51, 7.62] vs. 4.86 [3.36, 8.86] minutes; p  = 0.819), while discharge readiness was faster in the cipepofol group (1.67 [0.78, 2.38] vs. 2.96 [1.21, 7.23] minutes; p  = 0.002). Adverse events, including hypotension, bradycardia, and hypoxia, were comparable. Injection pain occurred only in the EP group (5%). Conclusion In older patients undergoing painless digestive endoscopy, cipepofol is non-inferior to the etomidate-propofol combination in sedation duration and safety. It also shares the characteristic of stable hemodynamics and offers advantages, including reduced injection pain and a shorter time to meet discharge criteria, providing a simplified choice for clinical practice. Trial registration ChiCTR2400088889, Date of Registration: 2024-08-28, https://www.chictr.org.cn/showproj.html?proj=212632 .

PurposeEtomidate and ketamine are hemodynamically stable induction agents often used to sedate critically ill patients during emergency endotracheal intubation. In 2015, quality improvement data from our hospital suggested a survival benefit at Day 7 from avoidance of etomidate in critically ill patients during emergency intubation. In this clinical trial, we hypothesized that randomization to ketamine instead of etomidate would be associated with Day 7 survival after emergency endotracheal intubation.MethodsA prospective, randomized, open-label, parallel assignment, single-center clinical trial performed by an anesthesiology-based Airway Team under emergent circumstances at one high-volume medical center in the United States. 801 critically ill patients requiring emergency intubation were randomly assigned 1:1 by computer-generated, pre-randomized sealed envelopes to receive etomidate (0.2–0.3 mg/kg, n = 400) or ketamine (1–2 mg/kg, n = 401) for sedation prior to intubation. The pre-specified primary endpoint of the trial was Day 7 survival. Secondary endpoints included Day 28 survival.ResultsOf the 801 enrolled patients, 396 were analyzed in the etomidate arm, and 395 in the ketamine arm. Day 7 survival was significantly lower in the etomidate arm than in the ketamine arm (77.3% versus 85.1%, difference − 7.8, 95% confidence interval − 13, − 2.4, p = 0.005). Day 28 survival rates for the two groups were not significantly different (etomidate 64.1%, ketamine 66.8%, difference − 2.7, 95% confidence interval − 9.3, 3.9, p = 0.294).ConclusionWhile the primary outcome of Day 7 survival was greater in patients randomized to ketamine, there was no significant difference in survival by Day 28.

BackgroundThe choice of anaesthetic agents may influence specific aspects of postoperative recovery, such as haemodynamic stability, recovery times and the incidence of adverse events, in patients undergoing day-case laparoscopic cholecystectomy. Propofol is widely used in total intravenous anaesthesia (TIVA) for its favourable recovery profile, while etomidate, valued for its haemodynamic stability, is less commonly used due to concerns about adrenal suppression. This study aims to compare etomidate-based and propofol-based TIVA on postoperative quality of recovery in patients undergoing day-case laparoscopic cholecystectomy, hypothesising that etomidate is non-inferior to propofol.Methods and analysisA multicentre, double-blind, randomised controlled non-inferiority trial was conducted to compare the effects of etomidate vs propofol for TIVA on postoperative quality of recovery in patients undergoing day-case laparoscopic cholecystectomy. A total of at least 336 participants were enrolled and randomly assigned to either the etomidate or propofol group in a 1:1 ratio, stratified by site. The primary outcome was quality of recovery on postoperative day 1, quantified by the Quality of Recovery-15 questionnaire. Non-inferiority between the groups was determined using a margin of −6 points and a 95% CI. Secondary outcomes included perioperative haemodynamic stability, recovery times (eg, response to verbal commands, time to extubation and duration of postanaesthesia care unit stay), postoperative complications (eg, hypoxaemia, nausea/vomiting, delirium) and patient-reported outcomes such as pain, satisfaction and quality of sleep. Long-term outcomes included quality of life at 6 and 12 months, assessed using the 36-Item Short Form Health Survey.Ethics and disseminationThis study was approved by the Ethics Committee of Nanjing University Medical School, Drum Tower Hospital (No. 2024-371-04) and registered in the Chinese Clinical Trial Registry.Trial registration numberChiCTR2400087413.

Background Tracheal intubation is a high-risk intervention commonly performed in critically ill patients. Due to its favorable cardiovascular profile, ketamine is considered less likely to compromise clinical outcomes. This meta-analysis aimed to assess whether ketamine, compared with other agents, reduces mortality in critically ill patients undergoing intubation. Methods We searched MEDLINE, Embase, and the Cochrane Library from inception until April 27, 2023, for randomized controlled trials and matched observational studies comparing ketamine with any control in critically ill patients as an induction agent. The primary outcome was mortality at the longest follow-up available, and the secondary outcomes included Sequential Organ Failure Assessment score, ventilator-free days at day 28, vasopressor-free days at day 28, post-induction mean arterial pressure, and successful intubation on the first attempt. For the primary outcome, we used a Bayesian random-effects meta-analysis on the risk ratio (RR) scale with a weakly informative neutral prior corresponding to a mean estimate of no difference with 95% probability; the estimated effect size will fall between a relative risk of 0.25 and 4. The RR and 95% credible interval (CrI) were used to estimate the probability of mortality reduction (RR < 1). The secondary outcomes were assessed with a frequentist random-effects model. We registered this study in Open Science Framework ( https://osf.io/2vf79/ ). Results We included seven randomized trials and one propensity-matched study totaling 2978 patients. Etomidate was the comparator in all the identified studies. The probability that ketamine reduced mortality was 83.2% (376/1475 [25%] vs. 411/1503 [27%]; RR, 0.93; 95% CrI, 0.79–1.08), which was confirmed by a subgroup analysis excluding studies with a high risk of bias. No significant difference was observed in any secondary outcomes. Conclusions All of the included studies evaluated ketamine versus etomidate among critically ill adults requiring tracheal intubation. This meta-analysis showed a moderate probability that induction with ketamine is associated with a reduced risk of mortality. Graphical abstract

IntroductionPost-induction hypotension (PIH) is a critical concern in elderly surgical patients and is associated with adverse postoperative outcomes. This trial aims to compare the effects of propofol, etomidate and remimazolam on the incidence of PIH in older adults undergoing non-cardiac surgery.Methods and analysisIn this single-centre, triple-arm, randomised controlled trial, 210 patients aged ≥80 years with American Society of Anaesthesiologists physical status I–III undergoing elective non-cardiac surgery will be recruited. All patients will receive general anaesthesia with endotracheal intubation. Patients will be randomised (1:1:1) to receive propofol, remimazolam or etomidate for anaesthesia induction (n=70 per group). The primary outcome is the incidence of PIH (mean arterial pressure (MAP) <65 mm Hg for 1 min) from induction initiation to surgical skin incision. Secondary outcomes include time to successful induction, time to tracheal intubation, MAP reduction >30% from baseline, vasopressor requirements, bradycardia, injection pain, myoclonus, postoperative delirium, and cardiac, cerebral and renal complications during hospitalisation.Ethics and disseminationThis trial was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University (Approval No. 2024-380). The results will be peer-reviewed for publication in a scientific journal.Trial registration numberChiCTR2400090800.

General anesthesia induced by etomidate, barbiturates and propofol is associated with positive modulation of synaptic αβγ GABAA receptors, inhibitory hetero-pentameric ligand-gated ion channels formed from homologous subunits arranged β-α-β-α-γ around a central gated chloride channel. Approaches based on mutations, amino-acid level analysis of photolabel incorporation, and cryo-electron micrography (cryo-EM) all indicate that etomidate binds selectively in two outer transmembrane β+/α- inter-subunit sites per receptor. These approaches also reveal that the potent barbiturate photolabel R-mTFD-MPAB binds selectively in homologous sites formed at α+/β- and γ+/β- interfaces. The anesthetic photolabel, pTFD-di-iPr-BnOH, was proposed to bind selectively in α+/β- and α+/γ- homologs of the etomidate sites, based largely on functional analysis of only 5 point mutations in α1β3γ2L receptors. To further test the interactions of receptor-bound pTFD-di-iPr-BnOH with outer transmembrane inter-subunit sites, we used voltage-clamp electrophysiology in substituted cysteine modification and protection (SCAMP) experiments at 8 residues located in the five homologous sites, focusing on α+ and γ- loci. Control SCAMP studies were performed using etomidate and R-mTFD-MPAB. Incorporation of single cysteine mutations (α1M236C, α1S280C, α1A291C, β3L231C, β3M286C, γ2I242C, γ2L246C, and γ2S301C) produced functional GABA-responsive receptors that retained sensitivity to pTFD-di-iPr-BnOH modulation and displayed increased GABA sensitivity following exposure to the covalent sulfhydryl modifier p-chloromercuribenzenesulfonate (pCMBS). In the presence of pTFD-di-iPr-BnOH, pCMBS modification effects were reduced (evidence of steric protection) in receptors with cysteine mutations in α+ , β-, and γ-, but not in α-, β+ , or γ+ interfacial loci. Protection patterns with etomidate and R-mTFD-MPAB mirrored prior results. SCAMP results further support the hypothesis that pTFD-di-iPr-BnOH binds selectively in α+/β- and α+/γ- interfacial sites that are homologs of the β+/α- etomidate sites.