Shared structural mechanisms of general anaesthetics and benzodiazepines.

Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABAA) receptors to dampen neuronal activity in the brain1-5. 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 GABAA 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 GABAA 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 GABAA 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.

Propofol vs etomidate for induction prior to invasive mechanical ventilation in patients with acute myocardial infarction.

BACKGROUND: Patients with acute myocardial infarction (AMI) requiring invasive mechanical ventilation (IMV) have a high mortality. However, little is known regarding the impact of induction agents, used prior to IMV, on clinical outcomes in this population. We assessed for the association between induction agent and mortality in patients with AMI requiring IMV. METHODS: We compared clinical outcomes between those receiving propofol compared to etomidate for induction among adults with AMI between October 2015 and December 2019 using the Vizient® Clinical Data Base, a multicenter, US national database. We used inverse probability treatment weighting (IPTW) to assess for the association between induction agent and in-hospital mortality. RESULTS: We identified 5,147 patients, 1,386 (26.9%) of received propofol and 3,761 (73.1%) received etomidate for IMV induction. The mean (SD) age was 66.1 (12.4) years, 33.0% were women, and 51.6% and 39.8% presented with STEMI and cardiogenic shock, respectively. Patients in the propofol group were more likely to require preintubation vasoactive medication and mechanical circulatory support (both, P < .05). Utilization of propofol was associated with lower mortality compared to etomidate (32.3% vs 36.1%, P = .01). After propensity weighting, propofol use remained associated with lower mortality (weighted mean difference -4.7%; 95% confidence interval: -7.6% to -1.8%, P = .002). Total cost, ventilator days, and length of stay were higher in the propofol group (all, P < .001). CONCLUSIONS: Induction with propofol, compared with etomidate, was associated with lower mortality for patients with AMI requiring IMV. Randomized trials are needed to determine the optimal induction agent for this critically ill patient population.

Etomidate versus Ketamine as Prehospital Induction Agent in Patients with Suspected Severe Traumatic Brain Injury.

BACKGROUND: Severe traumatic brain injury is a leading cause of morbidity and mortality among young people around the world. Prehospital care focuses on the prevention and treatment of secondary brain injury and commonly includes tracheal intubation after induction of general anesthesia. The choice of induction agent in this setting is controversial. This study therefore investigated the association between the chosen induction medication etomidate versus S(+)-ketamine and the 30-day mortality in patients with severe traumatic brain injury who received prehospital airway management in the Netherlands. METHODS: This study is a retrospective analysis of the prospectively collected observational data of the Brain Injury: Prehospital Registry of Outcomes, Treatments and Epidemiology of Cerebral Trauma (BRAIN-PROTECT) cohort study. Patients with suspected severe traumatic brain injury who were transported to a participating trauma center and who received etomidate or S(+)-ketamine for prehospital induction of anesthesia for advanced airway management were included. Statistical analyses were performed with multivariable logistic regression and inverse probability of treatment weighting analysis. RESULTS: In total, 1,457 patients were eligible for analysis. No significant association between the administered induction medication and 30-day mortality was observed in unadjusted analyses (32.9% mortality for etomidate versus 33.8% mortality for S(+)-ketamine; P = 0.716; odds ratio, 1.04; 95% CI, 0.83 to 1.32; P = 0.711), as well as after adjustment for potential confounders (odds ratio, 1.08; 95% CI, 0.67 to 1.73; P = 0.765; and risk difference 0.017; 95% CI, -0.051 to 0.084; P = 0.686). Likewise, in planned subgroup analyses for patients with confirmed traumatic brain injury and patients with isolated traumatic brain injury, no significant differences were found. Consistent results were found after multiple imputations of missing data. CONCLUSIONS: The analysis found no evidence for an association between the use of etomidate or S(+)-ketamine as an anesthetic agent for intubation in patients with traumatic brain injury and mortality after 30 days in the prehospital setting, suggesting that the choice of induction agent may not influence the patient mortality rate in this population.

Ketamine versus etomidate as an induction agent for tracheal intubation in critically ill adults: a Bayesian meta-analysis.

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.

Direct injection ultra-performance liquid chromatography-tandem mass spectrometry for the high-throughput determination of etomidate and etomidate acid in wastewater.

Etomidate (ET), a hypnotic agent used for the induction of anesthesia, is rapidly metabolized to etomidate acid (ETA) in the liver. Recently, ET has become one of the most serious alternative drugs of abuse in China. Therefore, an urgent need exists to develop a fast and convenient analysis method for monitoring ET. The current work presents a simple, fast, and sensitive direct injection method for the determination of ET and ETA in wastewater. After the optimization of the ultra-performance liquid chromatography-tandem mass spectrometry and sample filtration conditions, the method exhibited satisfactory limits of detection (1 ng/L) and good filtration loss. The validated method was successfully applied to determine the concentrations of ET and ETA in wastewater samples (n = 245) from several wastewater treatment plants in China. The concentrations of the targets in positive samples ranged from less than the lower limits of quantitation to 47.71 ng/L. The method can meet ET monitoring and high-throughput analysis requirements.

Effects of dexmedetomidine combined with etomidate on postoperative cognitive function in older patients undergoing total intravenous anaesthesia: a randomized, double-blind, controlled trial.

BACKGROUND: Etomidate has been advocated for anesthesia in older and critically ill patients because of its hemodynamic stability. Clinical studies have shown that dexmedetomidine has neuroprotective and anti-inflammatory properties and improves postoperative cognitive dysfunction in older patients. The present study was to evaluate the effects of the combination of etomidate and dexmedetomidine with different anaesthesia time on postoperative cognitive function in older patients. METHODS: A total of 132 older patients undergoing ureteroscopic holmium laser lithotripsy were randomly divided into EN group and ED group equally. Patients whose surgery time was less than or equal to 1 h in each group were allocated to short-time surgery group (EN1 group and ED1 group), and whose surgery time was more than 1h were allocated to long-term surgery group (EN2 group and ED2 group). The primary outcome was the score of the Mini-Mental State Examination. The secondary outcomes were State-Trait Anxiety Inventory scores, Riker sedation agitation scores, Zung Self-Rating Depression Scale scores, the memory span for Arabic numerals, the plasma concentrations of S-100 calcium-binding protein B and neuron specific enolase, the time to spontaneous respiration, recovery, and extubation. RESULTS: The MMSE scores at t2-3 were higher in ED1 and ED2 groups than in EN1 and EN2 groups (p<0.05). Compared with ED1 and ED2 groups, the ZSDS scores, the S-AI scores and the T-AI scores at t1-2 were higher in EN1 and EN2 groups (p<0.05), respectively. The recalled Arabic numbers at t1-3 were higher in ED2 group than in EN2 group (p<0.05). The plasma concentration of S-100ß at t1-2 in EN1 group and t1-3 in EN2 group were higher than that in ED1 and ED2 groups (p<0.05), respectively. Compared with ED1 and ED2 groups, the plasma concentrations of NSE were higher at t1-3 in EN1 group and t1-4 in EN2 group (p<0.05), respectively. CONCLUSION: The administration of dexmedetomidine could improve postoperative cognitive dysfunction, emergence agitation, depression and anxiety, attenuate the plasma concentrations of S-100ß and NSE in older patients undergoing total intravenous anaesthesia with etomidate. TRIAL REGISTRATION: Registration number: ChiCTR1800015421, Date: 29/03/2018.

Effects of different doses of alfentanil on cardiovascular response to rapid sequence intubation in elderly patients: a parallel-controlled randomized trial.

BACKGROUND: Rapid sequence intubation (RSI) have been shown to be effective in preventing reflux aspiration in patients with a full stomach during anaesthesia induction and endotracheal intubation. However, there is currently no standardized operation protocol or anaesthesia induction drug standard for RSI. Furthermore, there is a lack of evidence regarding the use of RSI in patients older than 65. In this study, we aimed to investigate the cardiovascular effects of different doses of alfentanil combined with propofol and etomidate during RSI in elderly patients aged 65-80 years. METHODS: A total of 96 patients aged 65-80 years who underwent general anaesthesia with tracheal intubation were selected for this study. The patients were randomly assigned to one of four groups using a random number table. Group A patients received an induction dose of 10 µg/kg alfentanil, group B patients received 15 µg/kg alfentanil, group C patients received 20 µg/kg alfentanil, and group D patients received 25 µg/kg alfentanil. Heart rate (HR), mean arterial pressure (MAP), cardiac index (CI), and ejection fraction (EF) were measured at three time points: 5 min before anaesthesia induction (T0), 1 min after endotracheal intubation (T1), and 5 min after endotracheal intubation (T2). Concurrently, 4 ml of arterial blood was collected from patients at three time points, and the concentrations of norepinephrine (NE) and cortisol (Cor) in plasma were detected. Occurrences of hypertension, hypotension, bradycardia and tachycardia during anesthesia induction to 5 min after tracheal intubation were noted. RESULTS: Compared with T0, the HR, MAP, NE and Cor concentrations in group A and group B were increased at the T1 and T2 time points, CI and EF values were decreased (P < 0.05). HR and MAP in groups C and D were increased at the T1 time point, while they were decreased at the T2 time point in group D (P < 0.05). The changes in CI and EF values, concentrations of NE and Cor, were not significant at T1 and T2 time points in group C (P > 0.05). Additionally, they were not significant in group D at the T1 time point (P > 0.05), but decreased at the T2 time point (P < 0.05). Compared with group A, the HR, MAP, NE and Cor concentrations in groups C and D were decreased at T1 and T2 time points (P < 0.05). The CI and EF values of groups C and D were increased at T1 time point but decreased at T2 time point in group D (P < 0.05). The incidence of hypertension and tachycardia in group A was significantly higher than that in group C and group D (P < 0.05), and the incidence of hypotension and bradycardia in group D was significantly higher than that in group A and group B (P < 0.05). CONCLUSION: Alfentanil 20 µg/kg for RSI in elderly patients, can effectively inhibit the violent cardiovascular reaction caused by intubation, and avoid the inhibition of cardiovascular system caused by large dose, hemodynamics more stable. TRIAL REGISTRATION: ChiCTR2200062034 ( www.chictr.org.cn ).

Etomidate inhibits tumor growth of glioblastoma by regulating M1 macrophage polarization.

Glioblastoma (GBM) is a common primary central nervous system tumor. Although the multimodal integrated treatment for GBM has made great progress in recent years, the overall survival time of GBM is still short. Thus, novel treatments for GBM are worth further investigation and exploration. This study aimed to investigate the effects of etomidate on GBM tumor growth and the underlying mechanism. A xenograft tumor model was established and treated with etomidate to assess tumor growth. Immunohistochemistry (IHC) assay evaluated the positive rate of Ki67 cells in tumor tissues. Cell counting kit (CCK)-8 and EdU assays accessed the cell viability and proliferation. Immunofluorescence (IF) staining detected the distribution of macrophage markers in tumor tissues. The percentages of M1- and M2-like macrophages in tumor-associated macrophages (TAMs) and co-culture system (macrophages and GBM cells) were detected using flow cytometry. Macrophage polarization-related genes were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Etomidate treatment inhibited the tumor growth, and increased the CD86+ cells but decreased the CD206+ cells in TAMs. The gene expression of M1 markers was increased in TAMs of etomidate-treated mice, whereas that of M2 markers was decreased. Moreover, etomidate treatment increased the number of CD86+ M1-like macrophages co-cultured with tumor cells but decreased that of CD206+ M2-like macrophages, with the upregulation of M1 markers and downregulation of M2 markers. Etomidate inhibited GBM tumor growth by promoting M1 macrophage polarization, suggesting a new insight into the clinical treatment of GBM.

The need to monitor emerging issues in etomidate usage: the misuse or abuse potential.

Since 2011, the misuse or abuse of etomidate has gradually increased when propofol was designated a controlled drug under the Narcotics Control Act in Korea. Accordingly, the Ministry of Food and Drug Safety announced that etomidate would be under the 'Regulation on the designation of drugs that may cause concerns of misuse or abuse' rule in June 2020, which is less stringent than the Narcotics Control Act. Therefore, this review investigates potential misuse or abuse cases of etomidate to consider strengthening its management. A literature search was conducted to compare etomidate with other sedatives in their efficacy and side effects, as well as identify the adverse health outcomes, abuse cases, and analytical methods of etomidate. Etomidate has an equal or higher sedative efficacy and lower risk of adverse cardiopulmonary events than propofol. However, major adverse effects of etomidate include adrenocortical suppression and unproven associated deaths, as well as myoclonus requiring pre-treatment. Although the issue of abuse and misuse of etomidate is emerging in recent years, there are few academic reports on these issues and analytical methods in the forensic field. In order to effectively manage the misuse or abuse of etomidate, it is necessary to continuously monitor related cases with great interest and to be more intensively studied on its abuse potential.

Substituted Cysteine Modification and Protection with n-Alkyl-MTS Reagents Quantifies Steric Changes Induced by a Mutation in Anesthetic Binding Sites on GABA Type A Receptors.

Multiple approaches, including cryogenic electron microscopy (cryo-EM), indicate that the anesthetics etomidate and propofol modulate α1ß2/3γ2 GABAA receptors by binding in overlapping transmembrane inter-subunit sites near ßM286 and αL232 sidechains. High-precision approaches in functional receptors are needed for comparisons with cryo-EM. We previously used substituted cysteine modification and protection (SCAMP) with n-alkyl-methanethiosulfonate (MTS) reagents and electrophysiology in α1ß3M286Cγ2L receptors to estimate the distance from etomidate to ß3M286 with precision near 1.3 Å. Here, we address three more aims using this approach: (i) SCAMP with etomidate was tested in α1L232Cß3γ2L receptors; (ii) studies in α1L232Wß3M286Cγ2L receptors assessed whether α1L232W displaces etomidate relative to ß3M286C; and (iii) results with propofol were compared with those with etomidate. Voltage-clamp electrophysiology in Xenopus oocytes was used to assess persistent functional changes after exposing cysteine-substituted receptors to methyl-MTS through n-decyl-MTS. Overlap of modified cysteine sidechains with bound anesthetic was inferred when anesthetic co-application with alkyl-MTS reagent blocked the development of persistent effects. In α1L232Cß3γ2L receptors, only pentyl-MTS and hexyl-MTS induced persistent effects that were unaltered by etomidate co-application, precluding a direct estimate of intermolecular distance. In α1L232Wß3M286Cγ2L receptors, sidechain overlap with bound etomidate was inferred for modifications with ethyl-MTS through n-pentyl-MTS, with unambiguous cut-on and cut-off. Comparison with results in α1ß3M286Cγ2L reveals that α1L232W, which increases maximal sidechain length by 2.1 Å, displaces etomidate closer to ß3M286C by about 1.3 Å. Propofol results largely mirrored those with etomidate. These findings indicate that both etomidate and propofol bind within 1 Å of α1L232, consistent with cryo-EM structures. SIGNIFICANCE STATEMENT: We combined electrophysiology, cysteine substitutions, and n-alkyl-methanethiosulfonate modifiers in functional GABAA receptors to enable precise estimates of the distance between ß3M286C sidechains and anesthetics (etomidate and propofol) bound in transmembrane ß+/α- inter-subunit pockets. Comparing results in α1ß3M286Cγ2L and α1L232Wß3M286Cγ2L receptors reveals that α1L232W mutations displace both anesthetics toward ß3M286C, indicating that these anesthetics bind within 1 Å of the α1L232 sidechain in functional receptors, consistent with cryogenic electron microscopy structures derived under nonphysiologic conditions.

Sedative Dose for Rapid Sequence Intubation and Postintubation Hypotension: Is There an Association?

STUDY OBJECTIVE: For patients with hemodynamic instability undergoing rapid sequence intubation, experts recommend reducing the sedative medication dose to minimize the risk of further hemodynamic deterioration. Scant data support this practice for etomidate and ketamine. We sought to determine if the dose of etomidate or ketamine was independently associated with postintubation hypotension. METHODS: We analyzed data from the National Emergency Airway Registry from January 2016 to December 2018. Patients aged 14 years or older were included if the first intubation attempt was facilitated with etomidate or ketamine. We used multivariable modeling to determine whether drug dose in milligrams per kilogram of patient weight was independently associated with postintubation hypotension (systolic blood pressure < 100 mm Hg). RESULTS: We analyzed 12,175 intubation encounters facilitated by etomidate and 1,849 facilitated by ketamine. The median drug doses were 0.28 mg/kg (interquartile range [IQR] 0.22 mg/kg to 0.32 mg/kg) for etomidate and 1.33 mg/kg (IQR 1 mg/kg to 1.8 mg/kg) for ketamine. Postintubation hypotension occurred in 1,976 patients (16.2%) who received etomidate and in 537 patients (29.0%) who received ketamine. In multivariable models, neither the etomidate dose (adjusted odds ratio [aOR] 0.95, 95% confidence interval [CI] 0.90 to 1.01) nor ketamine dose (aOR 0.97, 95% CI 0.81 to 1.17) was associated with postintubation hypotension. Results were similar in sensitivity analyses excluding patients with preintubation hypotension and including only patients intubated for shock. CONCLUSION: In this large registry of patients intubated after receiving either etomidate or ketamine, we observed no association between the weight-based sedative dose and postintubation hypotension.

Influences of Etomidate Combined with Propofol on Cognitive Function, Inflammation and Immunity in Patients Undergoing Gastric Cancer Surgery.

This study examined how etomidate combined with propofol affected cognitive function, inflammation, and immunity in patients undergoing gastric cancer surgery. 182 gastric cancer patients treated in our hospital were enrolled and randomly divided into two groups, namely group A (anesthetized using etomidate) and group B (anesthetized using etomidate combined with propofol). Then the cognitive function, inflammation and immunity indicators were determined in the two groups. Compared with group A, group B exhibited shorter operation duration and hospital stay and smaller bleeding volume (p<0.01). At 3 d after the operation, group B had a higher Ramsay score, but a lower visual analogue scale (VAS) score than group A (p<0.05). Moreover, the mini-mental state examination (MMSE) score was lower in group A than that in group B (p<0.01). At the end of the operation, the heart rate (HR), mean arterial pressure (MAP) and saturation of pulse oxygen (SpO2) were decreased to a great extent in both groups compared with those before anesthesia (p<0.05). Compared with those before anesthesia, the levels of immunoglobulin (Ig)M, IgG and IgA were lower in group A at the end of the operation and 1 and 3 d after the operation (p<0.05), but they were substantially higher in group B than those in group A (p<0.05). At the end of the operation and 1 and 3 d after the operation, the levels of the T-cell subset indicators decreases in group A were greater than those in group B (p<0.05). Etomidate combined with propofol has few influences on the immune and cognitive functions of gastric cancer patients and can effectively lower the expression levels of inflammatory factors in these patients.

Effects of Etomidate on Postintubation Hypotension, Inflammatory Markers, and Mortality in Critically Ill Patients with COVID-19: An International, Multicenter, Retrospective Study.

OBJECTIVE: To evaluate the association of etomidate with postintubation hypotension, inflammation, and mortality in critically ill patients with COVID-19. DESIGN: International, multicenter, retrospective study. PARTICIPANTS: Critically ill patients hospitalized specifically for COVID-19 from three major academic institutions in the US and Europe. MAIN OUTCOME AND MEASURES: Patients were allocated into the etomidate (ET) group or another induction agent (OA) group. The primary outcome was postintubation hypotension. Secondary outcomes included postintubation inflammatory status, in-hospital mortality, and mortality at 30 days. RESULTS: 171 patients with a median age of 68 (IQR 58-73) years were included (ET, n = 98; OA, n = 73). Etomidate was associated with lower postintubation mean arterial pressure [74.33 (64-85) mm Hg versus 81.84 (69.75-94.25) mm Hg, p = 0.005] compared to other agents. No statistically significant differences were generally observed in inflammatory markers between the two groups at 7- and 14-days after admission to the intensive care unit. In-hospital mortality [77 (79%) versus 41 (56%), p = 0.003] and mortality at 30-days [78 (80%) versus 43 (59%), p = 0.006] were higher in the ET group. In multivariate logistic regression analysis, only etomidate (p = 0.009) and postintubation mean arterial pressure (p < 0.001) had a statistically significant effect on mortality, in contrast to stress-dose steroids (p = 0.301), after adjusting for creatinine (p = 0.695), blood urea nitrogen (p = 0.153), age (p = 0.055), oxygen saturation of hemoglobin (SpO2) (p = 0.941), and fraction of inspired oxygen (FiO2) (p = 0.712). CONCLUSIONS: Administration of a single-bolus dose of etomidate in critically ill patients with COVID-19 is associated with lower postintubation mean arterial pressure and higher in-hospital and 30-day mortality compared to other induction agents.

Noninvasive Cardiac Output Monitoring (NICOM) in the Critically Ill Patient Undergoing Endotracheal Intubation: A Prospective Observational Study.

Background: Cardiovascular instability occurring during endotracheal intubation (ETI) in the critically ill is a commonly recognized phenomenon. However, this complication has not been evaluated in terms of the physiological cause (ie, decreased preload, contractility, or afterload) leading to the instability. Thus, the aim of the current investigation was to describe the hemodynamics occurring during ETI with noninvasive physiologic monitoring and to collect preliminary data on the hemodynamic effects of induction agents and positive pressure ventilation. Methods: A multicenter prospective study enrolling adult (≥18 years) critically ill patients undergoing ETI with noninvasive cardiac output monitoring in a medical/surgical intensive care unit from June 2018 to May 2019 was conducted. This study used the Cheetah Medical noninvasive cardiac output monitor to collect hemodynamic data during the peri-intubation period. Additional data collected included baseline characteristics such as illness severity, peri-intubation pharmacologic administration, and mechanical ventilation settings. Results: From the original 27 patients, only 19 (70%) patients had complete data and were included in the final analysis. Propofol was the most common sedative 8 (42%) followed by ketamine 6 (32%) and etomidate 5 (26%). Patients given propofol demonstrated a decrease in total peripheral resistance index (delta change [dynes × s/cm-5/m2]: -2.7 ± 778.2) but stabilization in cardiac index (delta change (L/min/m2]: 0.1 ± 1.5) while etomidate and ketamine demonstrated increases in total peripheral resistance index (etomidate delta change [dynes × s/cm-5/m2]: 302.1 ± 414.3; ketamine delta change [dynes × s/cm-5/m2]: 278.7 ± 418.9) but only etomidate resulted in a decrease in cardiac index (delta change [L/min/m2]: -0.3 ± 0.5). Positive pressure ventilation resulted in minimal changes to hemodynamics during ETI. Conclusions: The current study demonstrates that although propofol administration leads to a decrease in total peripheral resistance index, cardiac index is maintained while etomidate leads to a decrease in cardiac index with both etomidate and ketamine increasing total peripheral resistance index. These hemodynamic profiles are minimally affected by positive pressure ventilation. Study registration: ClinicalTrials.gov ID, NCT03525743.

The Impact of Inflammation and General Anesthesia on Memory and Executive Function in Mice.

BACKGROUND: Perioperative neurocognitive disorders (PNDs) are complex, multifactorial conditions that are associated with poor long-term outcomes. Inflammation and exposure to general anesthetic drugs are likely contributing factors; however, the relative impact of each factor alone versus the combination of these factors remains poorly understood. The goal of this study was to compare the relative impact of inflammation, general anesthesia, and the combination of both factors on memory and executive function. METHODS: To induce neuroinflammation at the time of exposure to an anesthetic drug, adult male mice were treated with lipopolysaccharide (LPS) or vehicle. One day later, they were anesthetized with etomidate (or vehicle). Levels of proinflammatory cytokines were measured in the hippocampus and cortex 24 hours after LPS treatment. Recognition memory and executive function were assessed starting 24 hours after anesthesia using the novel object recognition assay and the puzzle box, respectively. Data are expressed as mean (or median) differences (95% confidence interval). RESULTS: LPS induced neuroinflammation, as indicated by elevated levels of proinflammatory cytokines, including interleukin-1ß (LPS versus control, hippocampus: 3.49 pg/mg [2.06-4.92], P < .001; cortex: 2.60 pg/mg [0.83-4.40], P = .010) and tumor necrosis factor-α (hippocampus: 3.50 pg/mg [0.83-11.82], P = .002; cortex: 2.38 pg/mg [0.44-4.31], P = .021). Recognition memory was impaired in mice treated with LPS, as evinced by a lack of preference for the novel object (novel versus familiar: 1.03 seconds [-1.25 to 3.30], P = .689), but not in mice treated with etomidate alone (novel versus familiar: 2.38 seconds [0.15-4.60], P = .031). Mice cotreated with both LPS and etomidate also exhibited memory deficits (novel versus familiar: 1.40 seconds [-0.83 to 3.62], P = .383). In the puzzle box, mice treated with either LPS or etomidate alone showed no deficits. However, the combination of LPS and etomidate caused deficits in problem-solving tasks (door open task: -0.21 seconds [-0.40 to -0.01], P = .037; plug task: -0.30 seconds [-0.50 to -0.10], P < .001; log values versus control), indicating impaired executive function. CONCLUSIONS: Impairments in recognition memory were driven by inflammation. Deficits in executive function were only observed in mice cotreated with LPS and etomidate. Thus, an interplay between inflammation and etomidate anesthesia led to cognitive deficits that were not observed with either factor alone. These findings suggest that inflammation and anesthetic drugs may interact synergistically, or their combination may unmask covert or latent deficits induced by each factor alone, leading to PNDs.

Etomidate-Induced Myoclonus in Sprague-Dawley Rats Involves Neocortical Glutamate Accumulation and N -Methyl- d -Aspartate Receptor Activity.

BACKGROUND: Etomidate-induced myoclonus, a seizure-like movement, is of interest to anesthetists. However, its origin in the brain and its underlying mechanism remain unclear. METHODS: Adult male Sprague-Dawley rats were anesthetized with etomidate, propofol, or lidocaine plus etomidate. We assessed the incidence of myoclonus, behavioral scores, and levels of glutamate and γ-aminobutyric acid (GABA) in the neocortex and hippocampus. To determine the origin and how N -methyl- d -aspartate receptors (NMDARs) modulate etomidate-induced neuroexcitability, the local field potential and muscular tension were monitored. Calcium imaging in vitro and immunoblotting in vivo were conducted to investigate the mechanisms underlying myoclonus. RESULTS: The incidence of etomidate (1.5 mg/kg in vivo)-induced myoclonus was higher than that of propofol (90% vs 10%, P = .0010) and lidocaine plus etomidate (90% vs 20%, P = .0050). Etomidate at doses of 3.75 and 6 mg/kg decreased the mean behavioral score at 1 (mean difference [MD]: 1.80, 95% confidence interval [CI], 0.58-3.02; P = .0058 for both), 2 (MD: 1.60, 95% CI, 0.43-2.77; P = .0084 and MD: 1.70, 95% CI, 0.54-2.86; P = .0060), 3 (MD: 1.60, 95% CI, 0.35-2.85; P = .0127 and MD: 1.70, 95% CI, 0.46-2.94; P = .0091) minutes after administration compared to etomidate at a dose of 1.5 mg/kg. In addition, 0.5 and 1 µM etomidate in vitro increased neocortical intracellular calcium signaling; this signaling decreased when the concentration increased to 5 and 10 µM. Etomidate increased the glutamate level compared to propofol (mean rank difference: 18.20; P = .003), and lidocaine plus etomidate (mean rank difference: 21.70; P = .0002). Etomidate in vivo activated neocortical ripple waves and was positively correlated with muscular tension amplitude (Spearman's r = 0.785, P < .0001). Etomidate at 1.5 mg/kg decreased the K-Cl cotransporter isoform 2 (KCC2) level compared with propofol (MD: -1.15, 95% CI, -1.47 to -0.83; P < .0001) and lidocaine plus etomidate (MD: -0.64, 95% CI, -0.96 to -0.32; P = .0002), DL-2-amino-5-phosphopentanoic acid (AP5) suppressed these effects, while NMDA enhanced them. CONCLUSIONS: Etomidate-induced myoclonus or neuroexcitability is concentration dependent. Etomidate-induced myoclonus originates in the neocortex. The underlying mechanism involves neocortical glutamate accumulation and NMDAR modulation and myoclonus correlates with NMDAR-induced downregulation of KCC2 protein expression.

Application of low-dose etomidate combined with oxycodone and midazolam in endoscopic injection sclerotherapy.

OBJECTIVE: To evaluate the adverse effects and particularly the anesthetic effect of low-dose etomidate combined with oxycodone and midazolam in endoscopic injection sclerotherapy. MATERIALS AND METHODS: We herein report a prospective, double-blind, randomized controlled trial. It included patients with liver cirrhosis (age, 18 - 65 years; BMI, 18 - 25 kg/m2) who were treated with endoscopic injection sclerotherapy, and the patients were randomly assigned to the propofol group or the etomidate group. The incidence of respiratory depression was the primary outcome measure. The occurrence of various adverse effects and endoscopist satisfaction score were the secondary outcome measures. RESULTS: In this study, we enrolled a total of 96 patients. The incidence of respiratory depression in the propofol group was 19%, while that in the etomidate group was only 4% (9/47 vs. 2/49; p = 0.026). Regarding the secondary outcome measures, the incidence of hypoxia in the propofol group was 15%, while that in the etomidate group was only 2% (7/47 vs. 1/49; p = 0.029). Injection-site pain occurred in 0% and 23% of the patients in the etomidate group and propofol group, respectively (p < 0.001). Endoscopist satisfaction scores were classified as "poor", "fair", "good", and "very good". The scores were 17% higher (46/49 vs. 36/47; p = 0.026) for the "very good" level and 15% lower (3/49 vs. 10/47; p = 0.038) for the "good" level in the etomidate group than in the propofol group. CONCLUSION: Low-dose etomidate combined with oxycodone and midazolam for endoscopic injection sclerotherapy could reduce the incidence of hypoxia without increasing the incidence of complications.

Pharmacotherapy optimization for rapid sequence intubation in the emergency department.

PURPOSE: Rapid-sequence intubation (RSI) is the process of administering a sedative and neuromuscular blocking agent (NMBA) in rapid succession to facilitate endotracheal intubation. It is the most common and preferred method for intubation of patients presenting to the emergency department (ED). The selection and use of medications to facilitate RSI is critical for success. The purpose of this review is to describe pharmacotherapies used during the RSI process, discuss current clinical controversies in RSI medication selection, and review pharmacotherapy considerations for alternative intubation methods. SUMMARY: There are several steps to the intubation process requiring medication considerations, including pretreatment, induction, paralysis, and post-intubation sedation and analgesia. Pretreatment medications include atropine, lidocaine, and fentanyl; but use of these agents in clinical practice has fallen out of favor as there is limited evidence for their use outside of select clinical scenarios. There are several options for induction agents, though etomidate and ketamine are the most used due to their more favorable hemodynamic profiles. Currently there is retrospective evidence that etomidate may produce less hypotension than ketamine in patients presenting with shock or sepsis. Succinylcholine and rocuronium are the preferred neuromuscular blocking agents, and the literature suggests minimal differences between succinylcholine and high dose rocuronium in first-pass success rates. Selection between the two is based on patient specific factors, half-life and adverse effect profiles. Finally, medication-assisted preoxygenation and awake intubation are less common methods for intubation in the ED but require different considerations for medication use. AREAS FOR FUTURE RESEARCH: The optimal selection, dosing, and administration of RSI medications is complicated, and further research is needed in several areas. Additional prospective studies are needed to determine optimal induction agent selection and dosing in patients presenting with shock or sepsis. Controversy exists over optimal medication administration order (paralytic first vs induction first) and medication dosing in obese patients, but there is insufficient evidence to significantly alter current practices regarding medication dosing and administration. Further research examining awareness with paralysis during RSI is needed before definitive and widespread practice changes to medication use during RSI can be made.

Etomidate Depresses Spontaneous Complex Spikes Activity of Cerebellar Purkinje Cells via Cannabinoid 1 Receptor in vivo in Mice.

INTRODUCTION: Complex spikes (CSs) activity of cerebellar Purkinje cells plays critical roles in motor coordination and motor learning by transferring information to cerebellar cortex, which is an accessible and useful model for neurophysiological investigation. Etomidate is an ultrashort-acting nonbarbiturate intravenous anesthetic, which inhibits the spontaneous activity of cerebellar Purkinje cells through activation of GABAA and glycine receptors in vivo in mice. However, the effect of etomidate on the spontaneous CSs activity of cerebellar Purkinje cells in living mouse is not clear. METHODS: We here investigated the effects of etomidate on spontaneous CSs activity of cerebellar Purkinje cell in urethane-anesthetized mice by electrophysiology recording technique and pharmacological methods. RESULTS: Our results showed that cerebellar surface perfusion of etomidate significantly depressed the activity of spontaneous CSs, which exhibited decreases in the number of spikelets and the area under curve (AUC) of the CSs. The etomidate-produced inhibition of CSs activity was persisted in the presence of GABAA and glycine receptors antagonists. However, application of cannabinoid 1 (CB1) receptor antagonist, AM-251, completely blocked the etomidate-induced inhibition of CSs. Furthermore, application of the CB1 receptor agonist, WIN55212-2, induced a decrease of CSs. Moreover, in the presence of a specific protein kinase A (PKA) inhibitor, KT5720, etomidate failed to produce decreases in the spikelets number and the AUC of the spontaneous CSs. CONCLUSION: These results indicate that cerebellar surface application of etomidate facilitates CB1 receptor activity resulting in a depression of spontaneous CSs activity of Purkinje cells via PKA signaling pathway in mouse cerebellar cortex. Our present results suggest that the etomidate administration may impair the function of cerebellar cortical neuronal circuitry by inhibition of the climbing fiber - Purkinje cells synaptic transmission through activation of CB1 receptors in vivo in mice.

The effect-site concentration of remifentanil blunting endotracheal intubation responses during anesthesia induction with etomidate: a dose-finding study.

BACKGROUND: Remifentanil can inhibit the hemodynamic responses caused by endotracheal intubation, but the effect-site concentration of it required to control intubation responses when combined with etomidate has not been demonstrated. The purpose of this study was to determine the effect-site concentration of remifentanil blunting tracheal intubation responses in 50% and 95% of patients (EC50 and EC95) during etomidate anesthesia. METHODS: American Society of Anesthesiologists physical status (ASA) I-II elective surgical patients receiving target-controlled infusion (TCI) of remifentanil, followed by etomidate and rocuronium for anesthesia were enrolled. The Belive Drive A2 monitor was used to calculate the MGRSSI (Maygreen Sedative state index) of hypnotic effect and the MGRNOX (Maygreen Nociception index) of nociception. The MGRSSI and the MGRNOX value were generated every 1 s. Mean arterial pressure (MAP) and heart rate (HR) were measured every minute, noninvasively. Using the modified Dixon's up-and-down method, the concentration of remifentanil was determined based on the intubation response of the previous patient. The cardiovascular response during endotracheal intubation was defined as positive when MAP or HR is 20% higher than the pre-intubation value. A probit analysis was used for calculating EC50, EC95 and 95% confidence interval (CI). RESULTS: The EC50 and EC95 of remifentanil blunting tracheal intubation responses were found to be 7.731 ng/ml (95%CI: 7.212-8.278 ng/ml) and 8.701 ng/ml (95%CI: 8.199-11.834 ng/ml). There were statistically significant increases in HR, MGRSSI and MGRNOX value to tracheal intubation in the positive responses group compared to the negative group. The most common adverse event was postoperative nausea and vomiting, which occurred in 3 patients. CONCLUSION: Remifentanil effect-site concentration of 7.731 ng/ml is effective in blunting sympathetic responses to tracheal intubation in 50% of patients when combined with etomidate anesthesia. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trials Registry ( www.chictr.org.cn , registration number: ChiCTR2100054565, date of registration: 20/12/2021).