Long-term use of etomidate disrupts the intestinal homeostasis and nervous system in mice.

Etomidate (ETO) is used as an anesthetic in surgery, but it is being abused in some populations. The damage caused by long-term intake of ETO to intestinal and brain functions is not yet clear, and it remains to be determined whether the drug affects the central nervous system through the gut-brain axis. This study aimed to investigate the neurotoxic and gastrointestinal effects of ETO at doses of 1 mg/kg and 3 mg/kg in mice over 14 consecutive days. The results showed that long-term injection of ETO led to drug resistance in mice, affecting their innate preference for darkness and possibly inducing dependence on ETO. The levels of 5-hydroxytryptamine in the brain, serum, and colon decreased by 37%, 51%, and 42% respectively, while the levels of γ-aminobutyric acid reduced by 38%, 52%, and 41% respectively. H&E staining revealed that ETO reduced goblet cells in the colon and damaged the intestinal barrier. The expression of tight junction-related genes Claudin4 and ZO-1 was downregulated. The intestinal flora changed, the abundance of Akkermansia and Lactobacillus decreased by 33% and 14%, respectively, while Klebsiella increased by 18%. TUNEL results showed that high-dose ETO increased apoptotic cells in the brain. The expression of Claudin1 in the brain was downregulated. Untargeted metabolomics analysis of the colon and brain indicated that ETO caused abnormalities in glycerophospholipid metabolism. Abnormal lipid metabolism might lead to the production or accumulation of lipotoxic metabolites, causing central nervous system diseases. ETO induced changes in the intestinal flora and metabolism, further affecting the central nervous system through the gut-brain axis. The study unveiled the detrimental effects on the brain and gastrointestinal system resulting from long-term intake of ETO, which holds significant implications for comprehending the adverse impact of ETO abuse on human health.

Ratiometric determination of etomidate based on an albumin-based indicator displacement assay (IDA).

The first fluorescent sensor based on the indicator displacement assay (IDA) for on-site determination of etomidate.

Etomidate enhances cerebellar CF-PC synaptic plasticity through CB1 receptor/PKA cascade in vitro in mice.

Etomidate (ET) is a widely used intravenous imidazole general anesthetic, which depresses the cerebellar neuronal activity by modulating various receptors activity and synaptic transmission. In this study, we investigated the effects of ET on the cerebellar climbing fiber-Purkinje cells (CF-PC) plasticity in vitro in mice using whole-cell recording technique and pharmacological methods. Our results demonstrated that CF tetanic stimulation produced a mGluR1-dependent long-term depression (LTD) of CF-PC excitatory postsynaptic currents (EPSCs), which was enhanced by bath application of ET (10 µM). Blockade of mGluR1 receptor with JNJ16259685, ET triggered the tetanic stimulation to induce a CF-PC LTD accompanied with an increase in paired-pulse ratio (PPR). The ET-triggered CF-PC LTD was abolished by extracellular administration of an N-methyl-(D)-aspartate (NMDA) receptor antagonist, D-APV, as well as by intracellular blockade of NMDA receptors activity with MK801. Furthermore, blocking cannabinoids 1 (CB1) receptor with AM251 or chelating intracellular Ca2+ with BAPTA, ET failed to trigger the CF-PC LTD. Moreover, the ET-triggered CF-PC LTD was abolished by inhibition of protein kinase A (PKA), but not by inhibition of protein kinase C inhibiter. The present results suggest that ET acts on postsynaptic NMDA receptor resulting in an enhancement of the cerebellar CF-PC LTD through CB1 receptor/PKA cascade in vitro in mice. These results provide new evidence and possible mechanism for ET anesthesia to affect motor learning and motor coordination by regulating cerebellar CF-PC LTD.

Pharmacokinetic and pharmacodynamic evaluation study of etomidate: a randomized, open-label, 2-period crossover study in healthy Chinese subjects.

Etomidate is a sedative and hypnotic drug through intravenous administration that act on the central nervous system through GABA (Gamma-Amino Butyric Acid) receptors, which is widely used in anesthesia induction and maintenance and long-term sedation in severe patients. The study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of two etomidate fat emulsions after administration through the intravenous infusion pump in healthy Chinese subjects. A randomized, open-label, 2-period crossover study was performed in 52 healthy subjects. The wash-out period was 7 days. Blood samples and pharmacodynamic index values were collected at the specified time points. Etomidate concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were analyzed using a non-compartment model method. Pharmacodynamic parameters were calculated using pharmacodynamic index values. The study also evaluated the safety of the etomidate. Both the pharmacokinetic parameters and pharmacodynamic parameters result of the test and reference formulation were very similar. The 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratios of the test to reference formulation were 91.33-104.96% for the maximum plasma concentration (Cmax), 97.21-102.03% for the area under the plasma concentration time curve from time 0 to the time of the last measurable concentration (AUC0-t), and 97.22-102.33% for the area under the plasma concentration time curve from time 0 to infinity (AUC0-∞). Meanwhile, the 90% CI of the GLSM ratios of the test to reference formulation were 102.28-110.69% for the minimal BIS value (BISmin), 99.23-101.17% for the area under the BIS time curve from time 0-60 min after administration (BISAUC0-60 min), respectively. The 90% CI of these pharmacokinetic and pharmacodynamic parameters all fall in the accepted bioequivalence range of 80.00-125.00%. No serious adverse events occurred during the study. This study has shown that the etomidate fat emulsion test and reference formulation had similar pharmacokinetic and pharmacodynamic characteristics in vivo. The two formulations exhibited good safety and well-tolerance.Clinical trials registration number: http://www.chinadrugtrials.org.cn/index.html . # CTR20191836.

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 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.

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.

Promising activity of etomidate against mixed biofilms of fluconazole-resistant Candida albicans and methicillin-resistant Staphylococcus aureus.

Introduction. Candida albicans and Staphylococcus aureus are recognized for their development of resistance and biofilm formation. New therapeutic alternatives are necessary in this context.Hypothesis. Etomidate shows potential application in catheters against mixed biofilms of fluconazole-resistant C. albicans and methicillin-resistant S. aureus (MRSA).Aim. The present study aimed to evaluate the activity of etomidate against mixed biofilms of fluconazole-resistant C. albicans and MRSA.Methodology. The action of etomidate against mature biofilms was verified through the evaluation of biomass and cell viability, and its ability to prevent biofilm formation in peripheral venous catheters was determined based on counts of colony forming units (c.f.u.) and confirmed by morphological analysis through scanning electron microscopy (SEM).Results. Etomidate generated a reduction (P<0.05) in biomass and cell viability starting from a concentration of 250 µg ml-1. In addition, it showed significant ability to prevent the formation of mixed biofilms in a peripheral venous catheter, as shown by a reduction in c.f.u. SEM revealed that treatment with etomidate caused substantial damage to the fungal cells.Conclusion. The results showed the potential of etomidate against polymicrobial biofilms of fluconazole-resistant C. albicans and MRSA.

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.

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.

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.

The Effect of Propofol on Peri-Induction Hemodynamics and Resuscitation in Operative Penetrating Trauma.

BACKGROUND: Hemorrhaging trauma patients may be disproportionately affected by choice of induction agent during rapid sequence intubation (RSI). Etomidate, ketamine, and propofol are safe in the trauma population-at-large but have not been assessed in patients with ongoing hemorrhage. We hypothesize that in hemorrhaging patients with penetrating injury, propofol deleteriously affects peri-induction hypotension compared to etomidate and ketamine. METHODS: Retrospective cohort study. Primary outcome was the effect of induction agent on peri-induction systolic blood pressure. Secondary outcomes were the incidence of peri-induction vasopressor use and quantity of peri-induction blood transfusion requirements. Linear multivariate regression modeling assessed the effect of induction agent on the variables of interest. RESULTS: 169 patients were included, 146 received propofol and 23 received etomidate or ketamine. Univariate analysis revealed no difference in peri-induction systolic blood pressure (P = .53), peri-induction vasopressor administration (P = .62), or transfusion requirements within the first hour after induction (PRBC P = .24, FFP P = .19, PLT P = .29). Choice of RSI agent did not independently predict peri-induction systolic blood pressure or blood product administration. Rather, only presenting shock index independently predicted peri-induction hypotension. CONCLUSIONS: This is the first study to directly assess the peri-induction effects of anesthetic induction agent choice in penetrating trauma patients undergoing emergent hemorrhage control surgery. Propofol does not appear to worsen peri-induction hypotension regardless of dose. Patient physiology is most predictive of peri-induction hypotension.

Pharmacological interventions for reducing the incidence of myoclonus in patients receiving etomidate for induction of general anesthesia: an umbrella review.

OBJECTIVE: The objective of this umbrella review was to examine various pharmacologic interventions for their potential to reduce etomidate-induced myoclonus. A secondary objective was to compare the relative effectiveness of those medications in reducing the incidence of myoclonus when etomidate is utilized for the induction of general anesthesia. INTRODUCTION: Etomidate is the drug of choice when inducing general anesthesia in hemodynamically unstable patients. However, its use is limited among the general surgical population due to its ability to cause adrenal suppression, vomiting, and myoclonus. Myoclonus can lead to damage of muscle fibers, myalgias, and patient discomfort, and can also be detrimental in patients with low cardiac reserve. Several systematic reviews have reported on the effectiveness of various intravenous medications in reducing mild, moderate, and severe myoclonus; however, a more thorough examination of their influence was lacking. INCLUSION CRITERIA: This review included systematic reviews and meta-analyses of randomized controlled trials involving the use of pharmacologic interventions to reduce etomidate-induced myoclonus. Reviews in English and conducted after 1965 were considered for inclusion. METHODS: A comprehensive search of 11 databases was conducted to identify published and unpublished reviews up to March 2022. Critical appraisal was conducted by 2 independent reviewers using the standardized JBI appraisal tool. Quantitative findings were summarized according to the dose, timing of administration, and relative risk using a data matrix, and were synthesized in tabular format with supporting narrative text. Results were organized by severity of myoclonus (overall, mild, moderate, and severe) and by type of intervention. RESULTS: Eight systematic reviews were included in this umbrella review, which included 48 relevant studies, after removal of duplicates (3909 participants included in the primary studies). Five of the systematic reviews examined the effectiveness of various types of opioids in the prevention of myoclonus, and 3 systematic reviews examined the effectiveness of non-opioid interventions, such as lidocaine, midazolam, and dexmedetomidine. Seven reviews searched at least 4 databases for pertinent studies and specifically indicated that blinded reviewers appraised the articles. All reviews used a published and validated appraisal instrument. The overall quality of all included reviews was judged to be moderate to high. The absolute risk reduction indicating the effectiveness of the prophylactic medications ranged from 47% to 81% for mild, 52% to 92% for moderate, and 61% to 96% for severe myoclonus. Opioids demonstrated the most consistent and substantial effect on the reduction in myoclonus. CONCLUSIONS: All pharmacologic interventions identified in this review demonstrated a statistically significant reduction in the incidence of myoclonus. Future studies and reviews should focus on elucidating the particular dose range and timing that is most effective. Anesthesia providers should consider a pre-treatment dose of one of the medications described in this umbrella review as a means to reduce myoclonus and the untoward effects of that condition.