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.

Etomidate is devoid of genotoxicty and mutagenicity in human lymphocytes and in the Salmonella typhimurium/microsomal activation test.

No carcinogenesis or mutagenesis studies have been carried out with etomidate. The current study showed that etomidate has weak cytotoxic potential after 48 h exposure in human lymphocytes and has no hemolytic activity. The weak cytotoxicity seems to be related with redox imbalance of etomidate (40.9 and 81.9 µM) treated lymphocytes. At both etomidate concentrations, a slight decrease of the levels of GSH intracellular content and a significant increase in the amount of carbonylated proteins were observed after 48 h. The contribution of oxidative stress to genetic toxicity was only perceived when the enzyme Fpg was applied in the comet assay. Etomidate (40.9 and 81.9 µM) is a weak generator of oxidative DNA damage in lymphocytes. These damages to DNA probably were repaired, since no DNA strand breaks were detected in the standard alkaline comet assay (in the presence or absence of hepatic S9 microsomal fraction) without Fpg. Also, no micronucleated lymphocytes or carrying chromosomal aberrations were observed. Finally, etomidate (2046.8 and 4093.5 µM) was not mutagenic in the Salmonella/microsome mutagenicity assay, which used four Salmonella typhimurium strains (TA97a, TA98, TA100, and TA102) to detect frameshift and base-substitution mutations. In summary, etomidate is a weak oxidative DNA damaging anesthetic and is devoid of mutagenic properties in eukaryotic and prokaryotic models.

Hippocampal microglial activation triggers a neurotoxic-specific astrocyte response and mediates etomidate-induced long-term synaptic inhibition.

BACKGROUND: Accumulating 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. METHODS: A 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. RESULTS: We 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. CONCLUSIONS: A1-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.

An In Vitro Model for Identifying Cardiac Side Effects of Anesthetics.

The understanding of anesthetic side effects on the heart has been hindered by the lack of sophisticated clinical models. Using micropatterned human-induced pluripotent stem cell-derived cardiomyocytes, we obtained cardiac muscle depressant profiles for propofol, etomidate, and our newly identified anesthetic compound KSEB01-S2. Propofol was the strongest depressant among the 3 compounds tested, exhibiting the largest decrease in contraction velocity, depression rate, and beating frequency. Interestingly, KSEB01-S2 behaved similarly to etomidate, suggesting a better cardiac safety profile. Our results provide a proof-of-concept for using human-induced pluripotent stem cell-derived cardiomyocytes as an in vitro platform for future drug design.

Preclinical safety evaluation of ET-26 hydrochloride, a novel intravenous anesthetic agent, in beagle dogs.

ET-26 hydrochloride (ET-26HCl) is a novel etomidate analogue, approved for clinical trials, which has an effective sedative-hypnotic effect, a stable myocardial performance, and milder adrenocortical suppression than etomidate in rats and beagle dogs. Additionally, ET-26HCl showed similar hemodynamic stability as etomidate in the rat uncontrolled hemorrhagic shock model. Furthermore, ET-26HCl, in the rat lipopolysaccharide-induced sepsis model, was found to have a higher survival rate, a lower inflammatory reaction, and less organ injury. In the present study, we measured the potential adverse effects of ET-26HCl in beagle dogs in accordance with the Guidance on single- and repeated-dose toxicity published by the China Food and Drug Administration. In toxicity studies, single and repeated (14 days) intravenous doses of up to 16 mg/kg were well tolerated, with only pharmacologically related clinical signs seen in both studies. Thus, the no-observed-adverse-effect level (NOAEL) of ET-26HCl was found at 16 mg/kg/day. Toxicokinetic examination demonstrated that ET-26HCl showed a dose-dependent increase to exposure, no gender difference, and no evidence of accumulation. These results provide useful information for guiding a phase I clinical trial of ET-26HCl in healthy volunteers.

Determination of narcotic potency using a neurobehavioral assay with larval zebrafish.

BACKGROUND: Identifying chemicals with narcotic potency is an important aspect of assessing the safety of consumer products that may be accidentally ingested. A rapid and efficient assay of narcotic potency is desired for assessing chemicals with such suspected activity. OBJECTIVES: This purpose of this research was to develop a non-mammalian vertebrate, high throughput, neurobehavioral method to assess the narcotic potency of chemicals using larval zebrafish. METHODS: Larval zebrafish were acutely exposed to chemicals beginning at 5 days post fertilization (5 dpf). Locomotor activity, elicited by regular, periodic photostimulation, was quantified using a video tracking apparatus. Narcotic potency was determined as the molar concentration at which photostimulated locomotor activity was reduced by 50% (IC50). Toxicity was assessed based on observations of morbidity or mortality. Recovery was assessed following removal of test material by serial dilution and reassessment of photostimulated behavior 24 hr later (6 dpf). RESULTS: A total of 21 chemicals were assessed. Etomidate, a human narcotic analgesic agent, was used as a reference material. Investigating a series of eleven linear, primary alcohols (C6 to C16), a relationship between narcotic potency and carbon number was observed; narcotic potency increased with carbon number up to C12, consistent with historical studies. For a set of technical grade surfactants, nonionic surfactants (i.e., alcohol ethoxylates) were observed to be narcotic agents while anionic surfactants produced evidence of reduced locomotor activity only in combination with toxicity. Of the solvents evaluated, only ethanol exhibited narcotic activity with an IC50 of 261 mM and was the least potent of the chemicals investigated. Etomidate was the most potent material evaluated with an IC50 of 0.39 µM. CONCLUSIONS: The larval zebrafish neurobehavioral assay provides a method capable of estimating the narcotic potency of chemicals and can identify if toxicity contributes to observed neurobehavioral effects in the test organism.

Safety Evaluation of Sevoflurane as Anesthetic Agent in Mouse Model of Myocardial Ischemic Infarction.

The selection of anesthetics for patients with myocardial infarction is critically challenging. Sevoflurane is a volatile anesthetic gradually used in recent years. The intraoperative hemodynamic stability of sevoflurane was supported by several studies with some suggestions for its use for patients with cardiac events. The present study was undertaken to investigate the effect of sevoflurane on mice with myocardial infarction to evaluate the safety issue of this agent for possible application in patients with myocardial infarction. Mice of 7-12 weeks old were subjected to left anterior descending artery ligation to introduce acute myocardial infarction. The effect of sevoflurane on the hemodynamics was examined in comparison with that of currently available agent etomidate at low and moderate doses. The results showed that sevoflurane caused unstable hemodynamic changes in mice with myocardial infarction at both low and moderate inhaled concentrations relative to low and moderate doses of etomidate. In addition, the relative safety margin estimated from therapeutic index was decreased by 50 % when sevoflurane was used for mice with myocardial infarction relative to control mice, but only decreased by 20 % for etomidate. These analyses indicate that in comparison with currently available agent etomidate, sevoflurane should not be applied to patients with myocardial infarction or other cardiac events.

A Novel Strategy to Reverse General Anesthesia by Scavenging with the Acyclic Cucurbit[n]uril-type Molecular Container Calabadion 2.

BACKGROUND: Calabadion 2 is a new drug-encapsulating agent. In this study, the authors aim to assess its utility as an agent to reverse general anesthesia with etomidate and ketamine and facilitate recovery. METHODS: To evaluate the effect of calabadion 2 on anesthesia recovery, the authors studied the response of rats to calabadion 2 after continuous and bolus intravenous etomidate or ketamine and bolus intramuscular ketamine administration. The authors measured electroencephalographic predictors of depth of anesthesia (burst suppression ratio and total electroencephalographic power), functional mobility impairment, blood pressure, and toxicity. RESULTS: Calabadion 2 dose-dependently reverses the effects of ketamine and etomidate on electroencephalographic predictors of depth of anesthesia, as well as drug-induced hypotension, and shortens the time to recovery of righting reflex and functional mobility. Calabadion 2 displayed low cytotoxicity in MTS-3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium-based cell viability and adenylate kinase release cell necrosis assays, did not inhibit the human ether-à-go-go-related channel, and was not mutagenic (Ames test). On the basis of maximum tolerable dose and acceleration of righting reflex recovery, the authors calculated the therapeutic index of calabadion 2 in recovery as 16:1 (95% CI, 10 to 26:1) for the reversal of ketamine and 3:1 (95% CI, 2 to 5:1) for the reversal of etomidate. CONCLUSIONS: Calabadion 2 reverses etomidate and ketamine anesthesia in rats by chemical encapsulation at nontoxic concentrations.

The pituitary adenylate cyclase-activating polypeptide (PACAP) protects adrenal function in septic rats administered etomidate.

BACKGROUND: Both hyperinflammation during sepsis and etomidate can suppress adrenal function. In this study, we explored whether treatment with pituitary adenylate cyclase-activating polypeptide (PACAP) relieves adrenal suppression in cecal ligation and puncture (CLP)-induced septic rats. MATERIALS AND METHODS: Female Sprague-Dawley rats were randomly divided into five groups (n=7 per group), including the sham group, sepsis group (CLP group), sepsis and etomidate group (CLP+ETO group), PACAP group, and etomidate alone group (ETO group). Rats were sacrificed on the third day of sepsis, and blood and adrenal gland samples were obtained for further testing. RESULTS: The PACAP reduced the apoptosis rate of adrenal cells and peripheral lymphocytes, improving adrenal function, inhibiting the secretion of interferon gamma (IFN-γ) from peripheral lymphocytes, and slightly relieving the suppression of the adrenal function induced by the injection of etomidate in sepsis. CONCLUSION: In septic conditions, the PACAP protects the adrenal gland by regulating peripheral inflammation, which slightly relieves the toxic effects of etomidate on adrenal function.

Propofol, but not etomidate, increases corticosterone levels and induces long-term alteration in hippocampal synaptic activity in neonatal rats.

Animal studies provide strong evidence that general anesthetics (GAs), administered during the early postnatal period, induce long-term cognitive and neurological abnormalities. Because the brain growth spurt in rodents is delayed compared to that in humans, a fundamental question is whether the postnatal human brain is similarly vulnerable. Sevoflurane and propofol, GAs that share positive modulation of the gamma-aminobutyric acid type A receptor (GABAAR) function cause marked increase in corticosterone levels and induce long-term developmental alterations in synaptic activity in rodents. If synaptogenesis is affected, investigation of mechanisms of the synaptic effects of GAs is of high interest because synaptogenesis in humans continues for several years after birth. Here, we compared long-term synaptic effects of etomidate with those of propofol. Etomidate and propofol both positively modulate GABAAR activity, but in contrast to propofol, etomidate inhibits the adrenal synthesis of corticosterone. Postnatal day (P) 4, 5, or 6 rats received five injections of etomidate, propofol, or vehicle control during 5h of maternal separation. Endocrine effects of the anesthetics were evaluated by measuring serum levels of corticosterone immediately after anesthesia or maternal separation. The frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal CA1 pyramidal neurons were measured at P24-40 and P≥80. Only propofol caused a significant increase in serum corticosterone levels (F(4.26)=17.739, P<0.001). In contrast to increased frequency of mIPSCs in the propofol group (F(4.23)=8.731, p<0.001), mIPSC activity in the etomidate group was not different from that in the vehicle groups. The results of this study together with previously published data suggest that anesthetic-caused increase in corticosterone levels is required for GABAergic GAs to induce synaptic effects in the form of a long-term increase in the frequency of hippocampal mIPSCs.

Etomidate exposure in early infant mice (P10) does not induce apoptosis or affect behaviour.

BACKGROUND: Numerous animal studies have shown that all commonly used intravenous anaesthetic drugs and volatile agents may cause neuronal apoptosis following exposure in early life. Most studies have focussed on detecting increased apoptosis but their methods are not always readily transferrable to humans. The lipid formulation of etomidate represents an alternative to the currently established intravenous anaesthetic agents but there is no animal or human data on apoptosis or long-term behavioural changes. The aim of our study was to investigate the effects of etomidate on cerebral neuronal apoptosis and long-term behavioural effects using an established mouse model that represents the clinically relevant period of anaesthesia during early infancy in humans. METHODS: Six groups of 10 day old mice (P10) were injected with either etomidate 0.3, 3 or 10 mg/kg, propofol 60 mg/kg, ketamine 50 mg/kg or placebo only. Apoptosis in the cerebral cortex and hippocampus was assessed 24 h after treatment (activated caspase-3). Late behavioural effects were tested at 2 months of age (spontaneous activity in a new environment). RESULTS: No evidence was found of differences in activated caspase 3-concentrations among the study groups. Significant late behavioural changes were only observed in the ketamine group. CONCLUSION: A single dose of etomidate in early infant mice at P10 did not produce evidence of cerebral apoptosis or impaired adult motor behaviour.

Adrenocortical endocrine disruption.

The adrenal has been neglected in endocrine disruption regulatory testing strategy. The adrenal is a vital organ, adrenocortical insufficiency is recognised in life threatening "adrenal crises" and Addison's disease, and the consequences of off-target toxicological inhibition of adrenocortical steroidogenesis is well recognised in clinical medicine, where drugs such as aminoglutethimide and etomidate killed patients via unrecognised inhibition of adrenocortical steroidogenic enzymes (e.g. CYP11B1) along the cortisol and aldosterone pathways. The consequences of adrenocortical dysfunction during early development are also recognised in the congenital salt wasting and adrenogenital syndromes presenting neonatally, yet despite a remit to focus on developmental and reproductive toxicity mechanisms of endocrine disruption by many regulatory agencies (USEPA EDSTAC; REACH) the assessment of adrenocortical function has largely been ignored. Further, every step in the adrenocortical steroidogenic pathway (ACTH receptor, StAR, CYP's 11A1, 17, 21, 11B1, 11B2, and 3-hydroxysteroid dehydrogenase Δ4,5 isomerase) is known to be a potential target with multiple examples of chemicals inhibiting these targets. Many of these chemicals have been detected in human and wildlife tissues. This raises the question of whether exposure to low level environmental chemicals may be affecting adrenocortical function. This review examines the omission of adrenocortical testing in the current regulatory frameworks; the characteristics that make the adrenal cortex particularly vulnerable to toxic insult; chemicals and their toxicological targets within the adrenocortical steroidogenic pathways; the typical manifestations of adrenocortical toxicity (e.g. human iatrogenically induced pharmacotoxicological adrenal insufficiency, manifestations in typical mammalian regulatory general toxicology studies, manifestations in wildlife) and models of adrenocortical functional assessment. The utility of the in vivo ACTH challenge test to prove adrenocortical competency, and the H295R cell line to examine molecular mechanisms of steroidogenic pathway toxicity, are discussed. Finally, because of the central role of the adrenal in the physiologically adaptive stress response, the distinguishing features of stress, compared with adrenocortical toxicity, are discussed with reference to the evidence required to claim that adrenal hypertrophy results from stress rather than adrenocortical enzyme inhibition which is a serious adverse toxicological finding. This article is part of a special issue entitled 'Endocrine disruptors and steroids'.

Effects of Etomidate on the Steroidogenesis of Rat Immature Leydig Cells.

BACKGROUND: Etomidate is a rapid hypnotic intravenous anesthetic agent. The major side effect of etomidate is the reduced plasma concentration of corticosteroids, leading to the abnormal reaction of adrenals. Cortisol and testosterone biosynthesis has similar biosynthetic pathway, and shares several common steroidogenic enzymes, such as P450 side chain cleavage enzyme (CYP11A1) and 3ß-hydroxysteroid dehydrogenase 1 (HSD3B1). The effect of etomidate on Leydig cell steroidogenesis during the cell maturation process is not well established. METHODOLOGY: Immature Leydig cells isolated from 35 day-old rats were cultured with 30 µM etomidate for 3 hours in combination with LH, 8Br-cAMP, 25R-OH-cholesterol, pregnenolone, progesterone, androstenedione, testosterone and dihydrotestosterone, respectively. The concentrations of 5α-androstanediol and testosterone in the media were measured by radioimmunoassay. Leydig cells were cultured with various concentrations of etomidate (0.3-30 µM) for 3 hours, and total RNAs were extracted. Q-PCR was used to measure the mRNA levels of following genes: Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Srd5a1, and Akr1c14. The testis mitochondria and microsomes from 35-day-old rat testes were prepared and used to detect the direct action of etomidate on CYP11A1 and HSD3B1 activity. RESULTS AND CONCLUSIONS: In intact Leydig cells, 30 µM etomidate significantly inhibited androgen synthesis. Further studies showed that etomidate also inhibited the LH- stimulated androgen production. On purified testicular mitochondria and ER fractions, etomidate competitively inhibited both CYP11A1 and HSD3B1 activities, with the half maximal inhibitory concentration (IC50) values of 12.62 and 2.75 µM, respectively. In addition, etomidate inhibited steroidogenesis-related gene expression. At about 0.3 µM, etomidate significantly inhibited the expression of Akr1C14. At the higher concentration (30 µM), it also reduced the expression levels of Cyp11a1, Hsd17b3 and Srd5a1. In conclusion, etomidate directly inhibits the activities of CYP11A1 and HSD3B1, and the expression levels of Cyp11a1 and Hsd17b3, leading to the lower production of androgen by Leydig cells.

Comparison of the effects of four anaesthetics on haematological and blood biochemical profiles in pikeperch (Sander lucioperca L.).

OBJECTIVES: The objectives of the study were to compare the effects of Propiscin, 2-phenoxyethanol, clove oil and tricaine methane sulphonate (MS 222), anaesthetics frequently used in aquaculture. DESIGN: The haematological and biochemical blood profiles of pikeperch (Sander lucioperca L.) anesthetized with Propiscin (1.5 ml L-1), 2-phenoxyethanol (0.3 ml L-1), clove oil (33 mg L-1), MS 222 (150 mg L-1) and non-anesthetized control group were tested. Each tested group was divided into two subgroups, the first subgroup was sampled in anaesthesia 10 min after application of the anaesthetic and the second one live on 24h. RESULTS: The erythrocyte count and haematocrit was significantly decreased in 2-phenoxyethanol (24 h) compared with control group (CG). The mean corpuscular haemoglobin concentration was significantly increased in 2-phenoxyethanol (10 min), Propiscin (10 min and 24 h) compared to CG. The 2-phenoxyethanol (10 min and 24 h), MS 222 (24 h), clove oil (24 h), and Propiscin (10 min and 24 h) showed significantly lower leukocyte count compared with CG. The level of glucose was significantly (p<0.05) elevated with MS 222 (10 min) and clove oil (10 min) compared with CG. The 2-phenoxyethanol (10 min and 24 h), MS 222 (24 h), clove oil (24 h), and Propiscin (24 h) showed significantly lower (p<0.01) ammonia levels compared with CG. The triacylglycerols was significantly decreased (p<0.01) with Propiscin (10 min and 24 h), MS 222 (24 h), clove oil (24 h) and with 2-phenoxyethanol (24 h) compared with CG. After 24 hours MS 222 (24 h) and Propiscin (24 h) anaesthesia, fish showed significantly lower (p<0.01) concentration of inorganic phosphate compared with CG. CONCLUSIONS: On the basis of this experiment, it appears that clove oil was associated with the lowest effects in pikeperch and therefore would be recommended as an alternative to MS 222, while Propiscin and 2-phenoxyethanol are not suitable for manipulation with pikeperch in aquaculture.

Gamma-aminobutyric acid type A receptor ß3 subunit forebrain-specific knockout mice are resistant to the amnestic effect of isoflurane.

BACKGROUND: ß3 containing γ-aminobutyric acid type A receptors (GABA(A)-Rs) mediate behavioral end points of IV anesthetics such as immobility and hypnosis. A knockout mouse with targeted forebrain deletion of the ß3 subunit of the GABA(A)-R shows reduced sensitivity to the hypnotic effect of etomidate, as measured by the loss of righting reflex. The end points of amnesia and immobility produced by an inhaled anesthetic have yet to be evaluated in this conditional knockout. METHODS: We assessed forebrain selective ß3 conditional knockout mice and their littermate controls for conditional fear to evaluate amnesia and MAC, the minimum alveolar concentration of inhaled anesthetic necessary to produce immobility in response to noxious stimulation, to assess immobility. Suppression of conditional fear was assessed for etomidate and isoflurane, and MAC was assessed for isoflurane. RESULTS: Etomidate equally suppressed conditional fear for both genotypes. The knockout showed resistance to the suppression of conditional fear produced by isoflurane in comparison with control littermates. Controls and knockouts did not differ in isoflurane MAC values. CONCLUSIONS: These results suggest that ß3 containing GABA(A)-Rs in the forebrain contribute to hippocampal-dependent memory suppressed by isoflurane, but not etomidate.

The role of nitric oxide synthase inhibition in the adverse effects of etomidate in the setting of focal cerebral ischemia in rats.

We evaluated the effect of N(G)-nitro-L-arginine-methyl-ester (l-NAME, a nitric oxide synthase [NOS] inhibitor) and L-arginine (nitric oxide substrate) on cerebral mitochondrial dysfunction (hereafter referred to as "injury") after temporary middle cerebral artery occlusion (MCAo) during halothane or etomidate anesthesia in spontaneously hypertensive rats. Sixty minutes before MCAo, rats were randomized to 1 of 5 regimens (n = 8 per group): h/control, 1.2 minimum alveolar anesthetic concentration of halothane; h/L-NAME, 1.2 minimum alveolar anesthetic concentration of halothane and L-NAME (30 mg/kg); etomidate, an electroencephalographic (EEG) burst suppression dose of etomidate; e/L-NAME, an EEG burst suppression dose of etomidate and L-NAME (30 mg/kg); or e/L-NAME/arg, an EEG burst suppression dose of etomidate, L-NAME (30 mg/kg), and L-arginine (bolus of 300 mg/kg with an infusion at 35 mg x kg(-1) x min(-1)). After 180 min of MCAo and 120 min of reperfusion, volume of injury was determined using 2,3,5-triphenytetrazolium stain. Injury volume (mm(3), mean +/- sd) was larger in the etomidate group (153 +/- 17) than the halothane anesthetized h/control group (93 +/- 16) (P < 0.05) but did not differ between the e/L-NAME (162 +/- 17) and h/L-NAME groups (155 +/- 26). Injury volume in the e/L-NAME/arg group (88 +/- 15) was not different from the h/control group (93 +/- 16) and was less than that in either the etomidate or the e/L-NAME groups (P < 0.05). The data reproduce our previous observation that, relative to a halothane-anesthetized control state, etomidate has an adverse effect on ischemic injury in the setting of temporary focal cerebral ischemia. Prior inhibition of NOS with L-NAME resulted in no difference in the volume of injury between groups receiving etomidate or halothane (162 +/- 17 versus 155 +/- 26). Administration of a large dose of L-arginine prevented the adverse effect of etomidate. The data were obtained after only 2 h of reperfusion and therefore cannot be construed as representative of final neurologic outcome. They nonetheless suggest that etomidate produces an adverse effect on mitochondrial function early in the course of focal cerebral ischemia, in part, by inhibition of NOS.

Gamma-aminobutyric acid type A receptor beta 2 subunit mediates the hypothermic effect of etomidate in mice.

BACKGROUND: The authors have previously described that the gamma-aminobutyric acid type A (GABAA) receptor beta 2N265S mutation results in a knock-in mouse with reduced sensitivity to etomidate. After recovery from etomidate anesthesia, these mice have improved motor performance and less slow wave sleep. Because most clinically used anesthetics produce hypothermia, the effect of this mutation on core body temperature was investigated. METHODS: The effect of etomidate and propofol on core body temperature were measured using radiotelemetry in freely moving GABAA receptor beta 2N265S mutant mice and wild-type controls. RESULTS: beta 2N265S mutant mice have a reduced hypothermic response to anesthetic doses of etomidate compared with wild-type controls and after a transient loss of righting reflex regain normothermia more rapidly compared with wild-type controls. Subanesthetic doses of etomidate produce hypothermia, which was not observed in the mutant mice. Vehicle administration resulted in a stress-induced hyperthermic response in both genotypes. Propofol produced a hypothermic response that was similar in both genotypes. CONCLUSIONS: The GABAA receptor beta 2 subunit mediates a significant proportion of the hypothermic effects of etomidate. As the beta 2 subunit mediates postrecovery ataxia and sedation, anesthetic agents that do not have in vivo potency at beta 2 subunit-containing receptors offer the potential for surgical anesthesia with improved recovery characteristics.

Etomidate adversely alters determinants of left ventricular afterload in dogs with dilated cardiomyopathy.

UNLABELLED: We tested the hypothesis that etomidate produces similar alterations in left ventricular (LV) afterload in dogs with normal LV function or dilated cardiomyopathy. Dogs were instrumented for LV and aortic pressures, and aortic blood flow. LV afterload was measured with aortic input impedance and quantified with a three-element Windkessel model. In one group of experiments, dogs (n = 6) were paced at 240 bpm for 18 +/- 2 days (mean +/- SEM). Hemodynamic data were recorded in sinus rhythm in the conscious state and during etomidate anesthesia (5, 10, and 20 mg x kg(-1) x h(-1)). Identical experiments were conducted in a separate group of chronically instrumented dogs not subjected to LV pacing (n = 6). No changes in heart rate and arterial and LV pressures were observed during etomidate anesthesia in cardiomyopathic dogs. There were decreases in arterial and LV systolic pressure during the administration of 20 mg x kg(-1) x h(-1) etomidate to dogs with normal LV function. Etomidate significantly (P < 0.05) increased total arterial resistance (R; 3220 +/- 290 dynes x s x cm(-5) during control to 6110 +/- 790 dynes x s x cm(-5) during 10 mg x kg(-1) x h(-1)) and characteristic aortic impedance (Zc; 141 +/- 22 dynes x s x cm(-5) during control to 161 +/- 23 dynes x s x cm(-5) during 20 mg x kg(-1) x h(-1)) and decreased total arterial compliance (C; 0.70 +/- 0.15 mL/mm Hg during control to 0.45 +/- 0.07 mL/mm Hg during 10 mg x kg(-1) x h(-1)) in cardiomyopathic but not healthy dogs. Etomidate markedly reduced mean aortic blood flow (2.26 +/- 0.17 L/min during control to 1.39 +/- 0.20 L/min during 10 mg x kg(-1) x h(-1)) and increased the time constant of LV relaxation (54 +/- 3 ms during control to 74 +/- 9 ms during 20 mg x kg(-1) x h(-1)) in dogs with LV failure. Arterial pressure is maintained during etomidate anesthesia in the presence of LV dysfunction as a result of increases in R and Zc and decreases in C. These deleterious increases in LV afterload further compromise LV systolic and diastolic performance in dogs with dilated cardiomyopathy. IMPLICATIONS: The results of this investigation indicate arterial pressure is maintained during etomidate anesthesia as a consequence of increases in left ventricular (LV) afterload that further diminish LV systolic and diastolic performance in the presence of impaired LV function.

Focal cerebral ischemia during anesthesia with etomidate, isoflurane, or thiopental: a comparison of the extent of cerebral injury.

An investigation was performed to compare the cerebral protective properties of etomidate, isoflurane, and thiopental. In separate groups of spontaneously hypertensive rats, etomidate, isoflurane, or thiopental was administered to achieve and maintain burst-suppression of the electroencephalogram (3-5 bursts/min) for the duration of the experiment. A fourth group received 1.2 minimal alveolar concentration halothane. All groups underwent 3 hours of middle cerebral artery occlusion and then 2 hours of reperfusion. Thereafter, the animals were killed and the volume of injured brain was determined by staining with 2,3,5-triphenyltetrazolium. Physiological parameters did not differ among the four groups during the investigation, with the exception that hemolysis occurred in the etomidate group (free hemoglobin levels, approximately 0.4 g.dl-1). The volume of injured brain in the thiopental group (56 +/- 10 mm3) was significantly smaller than that in the halothane control group (99 +/- 13 mm3). The volumes of injured brain in the etomidate and isoflurane groups (145 +/- 11 mm3 and 139 +/- 14 mm3, respectively) were significantly larger than those in the control and thiopental groups. We speculate that the apparently detrimental effect of etomidate may be the result of the binding of nitric oxide of cerebral endothelial origin by the iron component of free hemoglobin. Intracranial pressure was not recorded, and in the isoflurane group, there may have been adverse effects on cerebral perfusion pressure associated with vasodilation caused by high concentrations of isoflurane. The results are consistent with a protective effect by barbiturates.

[Comparative studies of general anesthesia of sheep with ketamine and etomidate]. / Badania porównawcze nad ogólnym znieczuleniem owiec ketamina i etomidatem.

The studies were carried out on 48 sheep, 2-6 years old, weighing 33-67 kg. The animals were divided into two groups, 24 sheep each. From these 24, 16 sheep were tested for the plasma electrolytes contents, and 8 were tested for the acid-base balance and the oxygenation level of the arterial blood. Sheep from the first group were given xylasine in the dose of 0.1-10.3 mg/kg od body weight and etomidate (1 mg/kg of body weight). Sheep from the second group were given diazepam in the dose of 0.5 mg/kg of body weight and ketamine (20 mg/kg of body weight). In the first group the surgically effective anaesthesia lasting 15-20 minutes was obtained. During the anaesthesia a respiratory depression together with the decrease of oxygen saturation of the blood was observed. Also, a respiratory insufficiency leading to a respiratory acidosis, hypokalemia, hypocalcemia, hypomagnesemia and hypochloremia of plasma were observed. In the second group of sheep treated with ketamine and diazepam the increased pulse rate, respiratory insufficiency, hypokalemia, hypocalcemia and hypophosphatemia were observed. It has been said that respiratory and blood oxygenation disorders are the result of the forced long lasting position on one side. After treating with diazepam and ketamine bigger changes were observed. Usually all these changes and disorders recessed at the end of the experiment.