Etomidate

BackgroundAccumulating evidence has highlighted the importance of microglial and astrocyte responses in the pathological development of postoperative cognitive dysfunction (POCD). However, the mechanisms involved are not well understood.MethodsA perioperative neurocognitive disorders (PND) mouse model was generated by administering etomidate, and cognitive function was assessed using the Morris water maze and novel object recognition tests. Excitatory and inhibitory postsynaptic currents were recorded to analyze neuronal activity. In addition, microglia and astrocytes were isolated by magnetic-activated cell sorting, and genes that were activated in these cells were identified using quantitative polymerase chain reaction.ResultsWe observed dramatic cognitive impairment at 1 and 3 weeks after etomidate was administered to 18 month-old mice. Microglia and astrocytes isolated from the hippocampus showed significant microglial activation during the early pathological stage (i.e., 1 week after etomidate injection) and an A1-specific astrocyte response during the late pathological stage (i.e., 3 weeks after etomidate injection). Furthermore, when microglia were eliminated before etomidate was injected, the A1-specific astrocyte activation response was significantly reduced, and cognitive function improved. However, when microglia were eliminated after etomidate application, astrocyte activation and cognitive function were not significantly altered. In addition, activating microglia immediately after a sedative dose of etomidate was injected markedly increased A1-specific astrocyte activation and cognitive dysfunction.ConclusionsA1-specific astrocyte activation is triggered by activated microglia during the initial pathological stage of PND and induces long-term synaptic inhibition and cognitive deficiencies. These results improve our understanding of how PND develops and may suggest therapeutic targets.

Zebrafish are becoming one of the most used vertebrates in developmental and biomedical research. Fish are commonly killed at the end of an experiment with an overdose of tricaine methanesulfonate (TMS, also known as MS-222), but to date little research has assessed if exposure to this or other agents qualifies as euthanasia (i.e. a "good death"). Alternative agents include metomidate hydrochloride and clove oil. We use a conditioned place avoidance paradigm to compare aversion to TMS, clove oil, and metomidate hydrochloride. Zebrafish (n = 51) were exposed to the different anaesthetics in the initially preferred side of a light/dark box. After exposure to TMS zebrafish spent less time in their previously preferred side; aversion was less pronounced following exposure to metomidate hydrochloride and clove oil. Nine of 17 fish exposed to TMS chose not to re-enter the previously preferred side, versus 2 of 18 and 3 of 16 refusals for metomidate hydrochloride and clove oil, respectively. We conclude that metomidate hydrochloride and clove oil are less aversive than TMS and that these agents be used as humane alternatives to TMS for killing zebrafish.

BackgroundTracheal 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.MethodsWe 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 ResultsWe 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.ConclusionsAll 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.

ImportanceThe choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial.ObjectiveTo compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults.Design, setting, and participantsThis cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded.ExposureAdministration of etomidate or ketamine as the induction agent for RSI.Main outcomes and measuresThe primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups.ResultsAmong 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes.Conclusions and relevanceIn this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.