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PubMed1994

[TIVA with etomidate-fentanyl versus midazolam-fentanyl. The perioperative stress of coronary surgery overcomes the inhibition of cortisol synthesis caused by etomidate-fentanyl anesthesia].

Etomidate is a hypnotic with only minor effects on haemodynamics. Although its rapid elimination kinetics would suggest its use in total intravenous anaesthesia (TIVA) and sedation, its administration in higher doses or for a prolonged period has been discouraged due to its inhibitory effects on corticosteroid synthesis. Newer evidence that the suppression of cortisol synthesis might not be total requires a re-evaluation of this drug as a component of a TIVA technique. The effects of high-dose etomidate with fentanyl on spontaneous and stimulated corticosteroid levels as a measure of the magnitude and duration of adrenocortical suppression, as well as on plasma concentrations of adrenocorticotropic hormone (ACTH) beta-endorphin, and catecholamines during cardiac surgery were investigated in a prospective, randomised study and compared to those following the administration of midazolam-fentanyl. PATIENTS AND METHODS. Nineteen patients undergoing myocardial revascularisation were assigned to two groups: group 1: etomidate-fentanyl (n = 9) and group 2: midazolam-fentanyl (n = 10). Anaesthesia was induced with fentanyl 0.5 mg and either etomidate 0.3 mg/kg or midazolam 0.2 mg/kg. Relaxation was achieved with pancuronium 0.1 mg/kg. Anaesthesia was maintained during extracorporeal circulation (ECC) with an infusion of etomidate (0.36 mg.kg-1.h-1) or midazolam (0.16 mg.kg-1.h-1) and fentanyl 10 micrograms.kg-1.h-1. Blood samples were drawn before induction, before ECC, and 1, 6, and 20 h after surgery. Cortisol secretion was stimulated with 0.25 mg ACTH1-24 IV at 6 and 20 h postoperatively. RESULTS. The total drug doses were etomidate 87 +/- 3 mg and midazolam 46 +/- 2 mg. Plasma cortisol concentrations decreased in the etomidate group from 20 (10-31) to 10 (6-31) micrograms.dl-1 (median and range) before ECC, but had returned to baseline at 1 h and were significantly increased at 6 h [29 (15-47) micrograms.dl-1] and 20 h [46 (29-62) micrograms.dl-1]. There was no difference between the groups except at 20 h, when cortisol levels were higher in the etomidate group. The stimulated cortisol increase was markedly impaired in this group at both measuring points. ACTH and beta-endorphin were markedly increased in the etomidate group and ACTH concentrations were eight times greater than the corresponding values in the midazolam group after surgery (ACTH 141 vs. 18 pmol.l-1). Plasma catecholamine concentrations increased significantly in both groups. Noradrenaline concentrations were greater in the etomidate group at 6 h after surgery. Two patients in the midazolam group and none in the etomidate group required circulatory support with exogenous catecholamines. DISCUSSION. It is concluded that the stress of cardiac surgery can overcome the block in cortisol synthesis caused by the administration of high-dose etomidate by substantially increasing ACTH secretion. The administration of high-dose etomidate was not associated with cardiovascular instability. The use of etomidate as a component of TIVA can therefore not be ruled out on the grounds of insufficient cortisol secretion.

Adrenocorticotropic Hormone↗
PubMed1975

Etomidate, a potent non-barbiturate hypnotic. Intravenous etomidate in mice, rats, guinea-pigs, rabbits and dogs.

Etomidate, R-(+)-ethyl-1-(1-phenylethyl)-1H-imidazole-5-carboxylate was found to be a potent, short-acting and safe hypnotic; when given intravenously in single doses to mice, rats, guinea-pigs, rabbits and dogs. In rats of different body weight (50, 100, 200 and 300 g) two injection rates were used (2 sec and 2 min). By rapid iv injection in rats of 200 g etomidate (ED50 equal to 0.57 mg/kg) is about 6 times more potent than methohexital (ED50 equal to 3.51 mg/kg) and 25 times more potent than propanidid and thiopental (ED50's equal to 13.4 mg/kg). The safety margin (LD50/ED50) in these rats is 26.0 for etomidate, 9.5 for methohexital, 6.7 for propanidid and 4.6 for thiopental. Potency and toxicity of etomidate slightly increase with increasing injection rates without affecting the safety margin. The duration of hypnosis with etomidate is dose-dependent and the safety margin will therefore be widened when sleep of short duration is aimed at. Recovery after etomidate is very rapid. With lower body weights, higher doses in mg/kg are required for inducing hypnosis of comparable duration. No systematic differences were found after etomidate injection in incidence and duration of hypnosis nor in mortality between animals of different sex. ECG, blood pressure, haematological and biochemical analysis, urinalysis and histopathology did not reveal any drug-related adverse effect after daily injection of etomidate for 3 weeks in rats (highest dose 5.0 mg/kg) and 2 weeks in dogs (highest dose 1.50 mg/kg). No tolerance was observed after repeated administration. Etomidate is devoid of any teratogenic effect in rats (highest dose: 5.0 mg/kg daily from day 6 through day 15 of pregnancy), and in New Zealand white rabbits (highest dose: 4.5 mg/kg daily from day 6 through day 18 of pregnancy). The hypnotic effects of etomidate at very low dose levels in different laboratory animals are compared with the effects obtained in human subjects, in which successful induction of anaesthesia was obtained without producing any release of histamine and with only minimal effects on cardiovascular and respiratory functions.

Animals↗
PubMed1986

Changes in CMRO2, EEG and concentration of etomidate in serum and brain tissue during craniotomy with continuous etomidate supplemented with N2O and fentanyl.

Fourteen patients with supratentorial cerebral tumours were anaesthetized with continuous etomidate infusion (30 or 60 micrograms kg-1 min-1) supplemented with N2O 67% and fentanyl. Peroperatively cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were measured twice by the Kety and Schmidt method. Simultaneously with the CBF measurements, blood for serum etomidate was sampled and EEG was recorded in 2-min periods in 12 patients. In 10 patients a brain biopsy for etomidate was taken peroperatively and correlated with the other data. The results indicate a dose-dependant increase in serum etomidate and brain tissue etomidate, a decrease in CMRO2 and suppression of EEG activity. In individual studies an increase in serum etomidate or a decrease in CMRO2 correlated to a suppression of the EEG activity, and vice versa. However, the wide variations in these relationships within and between patients make any conclusion regarding CMRO2 impossible from the EEG recording, infusion rate of etomidate or serum concentration of etomidate.

Adult↗
PubMed1975

Distribution, metabolism and excretion of etomidate, a short-acting hypnotic drug, in the rat. Comparative study of (R)-(+)-(--)-Etomidate.

Tritium-labelled (R)-(+) and (S)-(--)-etomidate was injected intravenously in male Wistar rats at four dose levels. Initial plasma clearance was high and the largest part of etomidate was rapidly distributed over those tissues, that had entered in equilibrium with plasma, such as brain, erythrocytes, heart, spleen, lung, kidney, muscle and intestines. Only in subcutaneous fat, testicles and stomach peak levels appeared after 28 minutes. The levels of etomidate, observed in all these tissues varied proportionally with the dose. Although the contents in brain of thw two isomers were comparable, only (R)-(+)-etomidate possesses hypnotic activity. The concentration in brain of (R)-(+)-etomidate, producing hypnotic activity in rats, was 1.50 +/- 0.35 mug/g tissues. Peak levels in liver appeared shortly after administration. Capacity-limited ester hydrolysis in the liver was the main metabolic pathway, yielding a single amphoteric metabolite. The rate of metabolization of (R)-(+)-etomidate was higher than that of the (S)-(--)-isomer. Excretion of the metabolite was mainly with the urine.

Animals↗
PubMed2000

Does etomidate increase postoperative nausea? A double-blind controlled comparison of etomidate in lipid emulsion with propofol for balanced anaesthesia.

In a double-blind randomized study, the incidence and severity of postoperative nausea and vomiting was investigated with a new formulation of etomidate (Etomidate-(R)Lipuro, B. Braun Melsungen AG, Germany) compared with propofol for induction of a balanced anaesthesia with isoflurane/fentanyl in air. The incidence and intensity of nausea was examined by use of a visual analogue scale (VAS; 0-100 mm) at 1, 2, between 6 and 8, and 24 h postoperatively. One-hundred-and-sixty-four patients undergoing orthopedic procedures were studied. For etomidate vs. propofol, 14.6% vs. 14.2% male and 26.8% vs. 27.5% female patients were nauseated during the first two postoperative hours. The median rating for nausea remained below 5 mm at any time in both groups, i.e. the intensity of nausea was very low. The incidence of vomiting was higher in women receiving etomidate (26.8% vs. 10%). We conclude that etomidate does not increase nausea during the early postoperative period.

Adult↗
PubMed1988

[Etomidate versus etomidate and hydrocortisone for anesthesia induction in abdominal surgical interventions].

The imidazole derivative etomidate has been shown to block (reversibly) adrenocortical steroid synthesis. Long-term sedation with etomidate has been associated with adrenocortical insufficiency and increased mortality in severely ill patients. The significance of adrenocortical blockade after a single induction dose of etomidate remains a matter of debate. This study was designed to analyze the role of glucocorticoid deficiency after a single induction dose of etomidate for major surgery. In a prospective controlled double-blind study, 20 consecutive patients scheduled for colorectal surgery were randomly allocated to either hydrocortisone substitution or placebo (glucose 5%). Hydrocortisone was given as a continuous infusion in a dose of 100 mg dissolved in 5% glucose over 10 h. We combined general anesthesia and epidural anesthesia (L3-4) using bupivacaine (0.5%). Induction of anesthesia: etomidate (0.2-0.3 mg/kg), fentanyl (0.1-0.2 mg), pancuronium (2 mg), and succinyl-choline (1.0-1.5 mg/kg), with endotracheal intubation and mechanical ventilation. Anesthesia was maintained at N2O/O2 2:1 and fluothane (0.4-0.6 vol%). At the end of surgery patients were extubated after oxygenation. In all patients blood pressure, heart rate, central venous pressure, and ECG were monitored continuously, both intra- and postoperatively. During induction, patients received 1,000 ml 0.9% NaCl, followed by continuous administration of 0.9% NaCl, 6 ml/kg per hour intraoperatively and 40 ml/kg per 24 hours post-operatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Insufficiency↗
PubMed1983

High-performance liquid chromatographic assay for etomidate in human plasma: results of preliminary clinical studies using etomidate for hypnosis in total intravenous anesthesia.

A sensitive and specific high-performance liquid chromatographic assay was developed for the measurement of etomidate in human plasma following extraction of the drug and the internal standard. Using 0.5-ml aliquots of plasma, the assay was linear in the concentration range of 20-2000 ng of etomidate/ml of plasma. This method was used to evaluate a preliminary clinical study of an etomidate infusion regimen for hypnosis in a total intravenous anesthesia protocol in 23 patients. The average duration of the infusion was 30 min, and awakening and alertness occurred 20 and 36 min after the termination of the infusion, respectively, at the respective plasma concentrations of 297 and 214 ng/ml. These results and this assay will be used to design and evaluate an improved etomidate infusion regimen.

Anesthesia, Intravenous↗
PubMed1990

[Etomidate using a new solubilizer. Experimental clinical studies on venous tolerance and bioavailability].

Pain following intravenous injection as well as thrombophlebitis are substantial side effects of etomidate that have been reported from the first clinical study (1972-1973) onwards. Investigations of our own and by Gran et al. have pointed out that injectable etomidate with intralipid as a solvent removes side effects without impairing the good hypnotic action. The idea of using a lipid emulsion as a solvent was presented a few years later, inducing two further studies. METHOD. Both pharmacodynamic (continuous EEG registration) and pharmacokinetic [determination (HPLC) of plasma levels of the active substance] investigations were carried out on volunteers. At random 16 volunteers received etomidate in propylene glycol or etomidate in lipid emulsion for general anesthesia. A dose of 0.3 mg kg-1 was given over 60 s. In a clinical study 100 patients were divided into two independent groups of 50 each. They received either the commercially available etomidate in 35% propylene glycol (group I) or the new formulation containing 20 mg etomidate in 10 ml of a lipid-emulsion (Lipofundin MCT 20%) (group II). A dose of 0.3 mg kg-1 etomidate was given. RESULTS. There was a higher concentration of etomidate for 8 min after injection in lipid emulsion compared with etomidate in propylene glycol. The plasma concentration of etomidate (200 ng/ml) correlates with C2 corresponding to the light sleep stage after etomidate in propylene glycol, but with D0 according to the deep sleep stage after etomidate in lipid emulsion. At lower plasma concentrations, the hypnotic action of etomidate in propylene glycol is stronger than the effect of the lipid emulsion. This result means that it is possible that a part of the etomidate remains in the lipid particles. In the clinical study the anesthetic induction time was nearly identical in both groups; blood pressure and heart rate were stable. Following etomidate in propylene glycol, 36% of the patients complained of a painful injection. On the first postoperative day, 9 of 47 patients showed signs of phlebitis and three others thrombosis. On the 7th day a venous reaction was evident in 22% of these patients; 2 patients had developed phlebitis, 5 thrombosis and 4 thrombophlebitis. After etomidate in lipid emulsion, there were no signs of local irritation. The same results have been obtained in the study with volunteers. CONCLUSION. Two unpleasant side effects of etomidate, pain on injection and postoperative thrombophlebitis, were abolished by the solvent "lipid emulsion".

Adult↗
PubMed1998

Buccal absorption of etomidate from a solid formulation in dogs.

UNLABELLED: Etomidate is typically administered i.v. for the induction of general anesthesia. We believe that oral transmucosal absorption may extend etomidate's use to premedication and conscious sedation. Our objective was to study the oral mucosal absorption kinetics and bioavailability of etomidate in a solid dose form in dogs. A solid dose form containing 50 mg of etomidate in sorbitol for buccal administration was prepared. Each dog was administered both i.v. etomidate and buccal etomidate on separate days. Serum etomidate concentrations after i.v. administration were fit to a two-compartment pharmacokinetic model. The rates at which etomidate enters the systemic circulation via buccal mucosal absorption were calculated from serum concentrations from mucosal and i.v. administrations using model-dependent constrained numerical deconvolution. The apparent permeability coefficient and bioavailability were also determined. The mean (+/- SD) maximal serum etomidate concentration after buccal mucosal absorption from the 50-mg dose unit was 239 +/- 79 ng/mL. The time to reach maximal serum concentration was 12.5 +/- 1.8 min. Peak absorption rate of etomidate into the systemic circulation was 832 +/- 417 microg/min. For all dogs, 90% or more of the absorption via buccal mucosa took place during the period in which the drug was in contact with the mucosa (15 min). The apparent transbuccal mucosal permeability coefficient was 9.1 +/- 4.2 x 10(-4) cm/s, higher than values of any other compounds examined. Bioavailability calculated using the area under the serum etomidate concentration versus time curve method and the deconvolution method was 13.6% +/- 10.7% and 16.6% +/- 7.6%, respectively. In conclusion, etomidate is highly permeable through the canine buccal mucosa. IMPLICATIONS: Etomidate is highly permeable through the canine buccal mucosa. Both the onset and the termination of buccal mucosal absorption of etomidate are rapid, which suggests that titratable delivery of etomidate may be possible by buccal administration.

Absorption↗
PubMed2006

Randomized clinical trial of etomidate versus propofol for procedural sedation in the emergency department.

STUDY OBJECTIVE: We compare the efficacy, adverse events, and recovery duration of etomidate and propofol for use in procedural sedation in the emergency department (ED). METHODS: This was a randomized nonblinded prospective trial of adult patients undergoing procedural sedation for painful procedures in the ED. Patients received either propofol or etomidate. Doses, vital signs, nasal end-tidal CO2 (ETCO2), pulse oximetry, and bispectral electroencephalogram analysis scores were recorded. Subclinical respiratory depression was defined as a change in ETCO2 greater than 10 mm Hg, an oxygen saturation of less than 92% at any time, or an absent ETCO2 waveform at any time. Clinical events related to respiratory depression, including an increase in supplemental oxygen, the use of a bag-valve-mask apparatus, airway repositioning, or stimulation to induce breathing, were noted during the procedure. After the procedure, patients completed visual analog scales about perceived pain during the procedure and recall of the procedure. RESULTS: Two hundred twenty patients were enrolled; 214 underwent sedation and were analyzed. One hundred five patients received etomidate and 109 received propofol. No clinically significant complications were noted. Subclinical respiratory depression was observed in 36 of 105 (34.3%) patients in the etomidate group and 46 of 109 (42.2%) in the propofol group (difference -7.9%; 95% confidence interval [CI] -20.9% to 5.1%). Myoclonus was noted in 21 of 105 (20.0%) patients in the etomidate group and 2 of 109 (1.8%) in the propofol group (difference 18.2%; 95% CI 10.1% to 26.2%). The mean difference between baseline systolic blood pressure and the nadir was 3.8% (95% CI 2.3% to 5.3%) for etomidate and 7.9% (95% CI 6.1% to 9.7%) for propofol. Clinical events related to respiratory depression included an increase in supplemental oxygen in 6.7% of etomidate patients and 5.5% of propofol patients (difference 1.2%; 95% CI -5.2% to 7.6%), the use of bag-valve-mask apparatus in 3.8% of patients in the etomidate groups and 4.6% in the propofol group (difference -0.8%; 95% CI -6.1% to 4.6%), airway repositioning in 13.3% of etomidate patients and 11.0% of propofol patients (effect size 2.3%; 95% CI -6.4% to 11.1%), and stimulation to induce breathing in 11.4% of etomidate patients and 11.9% of propofol patients (difference -0.5%; 95% CI -9.1% to 8.1%). The procedures were successful in 93 of 105 (88.6%) for etomidate and 106 of 109 (97.2%) for propofol (difference -7.4%; 95% CI -14.3% to -1.1%). CONCLUSION: Etomidate and propofol appear equally safe for ED procedural sedation; however, etomidate had a lower rate of procedural success and induced myoclonus in 20% of patients.

Adolescent↗
PubMed1998

The effect of a transmembrane amino acid on etomidate sensitivity of an invertebrate GABA receptor.

1. The gamma-aminobutyric acid (GABA)-modulatory and GABA-mimetic actions of etomidate at mammalian GABA(A) receptors are favoured by beta2- or beta3- versus beta1-subunit containing receptors, a selectivity which resides with a single transmembrane amino acid (beta2 N290, beta3 N289, beta1 S290). Here, we have utilized the Xenopus laevis oocyte expression system in conjunction with the two-point voltage clamp technique to determine the influence of the equivalent amino acid (M314) on the actions of this anaesthetic at an etomidate-insensitive invertebrate GABA receptor (Rdl) of Drosophila melanogaster. 2. Complementary RNA-injected oocytes expressing the wild type Rdl GABA receptor and voltage-clamped at -60 mV responded to bath applied GABA with a concentration-dependent inward current response and a calculated EC50 for GABA of 20+/-0.4 microM. Receptors in which the transmembrane methionine residue (M314) had been exchanged for an asparagine (RdlM314N) or a serine (RdlM314S) also exhibited a concentration-dependent inward current response to GABA, but in both cases with a reduced EC50 of 4.8+/-0.2 microM. 3. Utilizing the appropriate GABA EC10, etomidate (300 microM) had little effect on the agonist-evoked current of the wild type Rdl receptor. By contrast, at RdlM314N receptors, etomidate produced a clear concentration-dependent enhancement of GABA-evoked currents with a calculated EC50 of 64+/-3 microM and an Emax of 68+/-2% (of the maximum response to GABA). 4. The actions of etomidate at RdlM314N receptors exhibited an enantioselectivity common to that found for mammalian receptors, with 100 microM R-(+)-etomidate and S-(-)-etomidate enhancing the current induced by GABA (EC10) to 52+/-6% and 12+/-1% of the GABA maximum respectively. 5. The effects of this mutation were selective for etomidate as the GABA-modulatory actions of 1 mM pentobarbitone at wild type Rdl (49+/-4% of the GABA maximum) and RdlM314N receptors (53+/-2% of the GABA maximum) were similar. Additionally, the modest potentiation of GABA produced by the anaesthetic neurosteroid 5alpha-pregnan-3alpha-ol-20-one (Rdl = 25+/-4% of the GABA maximum) was not altered by this mutation (RdlM314N = 18+/-3% of the GABA maximum). 6. Etomidate acting at beta1 (S290)-containing mammalian GABA(A) receptors is known to produce only a modest GABA-modulatory effect. Similarly, etomidate acting at RdlM314S receptors produced an enhancement of GABA but the magnitude of the effect was reduced compared to RdlM314N receptors. 7. Etomidate acting at human alpha6beta3gamma2L receptors is known to produce a large enhancement of GABA-evoked currents and at higher concentrations this anaesthetic directly activates the GABA(A) receptor complex. Mutation of the human beta3 subunit asparagine to methionine (beta3 N289M found in the equivalent position in Rdl completely inhibited both the GABA-modulatory and GABA-mimetic action of etomidate (10-300 microM) acting at alpha6beta3 N289Mgamma2L receptors. 8. It was concluded that, although invertebrate and mammalian proteins exhibit limited sequence homology, allosteric modification of their function by etomidate can be influenced in a complementary manner by a single amino acid substitution. The results are discussed in relation to whether this amino acid contributes to the anaesthetic binding site, or is essential for transduction. Furthermore, this study provides a clear example of the specificity of anaesthetic action.

Allosteric Regulation↗
PubMed2004

Gating allosterism at a single class of etomidate sites on alpha1beta2gamma2L GABA A receptors accounts for both direct activation and agonist modulation.

At clinical concentrations, the potent intravenous general anesthetic etomidate enhances gamma-aminobutyric acid, type A (GABA(A)) receptor activity elicited with low gamma-aminobutyric acid (GABA) concentrations, whereas much higher etomidate concentrations activate receptors in the absence of GABA. Therefore, GABA(A) receptors may possess two types of etomidate sites: high affinity GABA-modulating sites and low affinity channel-activating sites. However, GABA modulation and direct activation share stereoselectivity for the (R)(+)-etomidate isomer and display parallel dependence on GABA(A) beta subunit isoforms, suggesting that these two actions may be mediated by a single class of etomidate site(s) that exert one or more molecular effects. In this study, we assessed GABA modulation by etomidate using leftward shifts of electrophysiological GABA concentration responses in cells expressing human alpha1beta2gamma2L receptors. Etomidate at up to 100 microm reduced GABA EC(50) values by over 100-fold but without apparent saturation, indicating the absence of high affinity etomidate sites. In experiments using a partial agonist, P4S, etomidate both reduced EC(50) and increased maximal efficacy, demonstrating that etomidate shifts the GABA(A) receptor gating equilibrium toward open states. Results were quantitatively analyzed using equilibrium receptor gating models, wherein a postulated class of equivalent etomidate sites both directly activates receptors and enhances agonist gating. A Monod-Wyman-Changeux co-agonist mechanism with two equivalent etomidate sites that allosterically enhance GABA(A) receptor gating independently of agonist binding most simply accounts for direct activation and agonist modulation. This model also correctly predicts the actions of etomidate on GABA(A) receptors containing a point mutation that increases constitutive gating activity.

Allosteric Site↗
PubMed1990

In vitro effects of etomidate on intrinsic myocardial contractility in the rat.

Etomidate is available in two different solvents: propylene glycol for induction of anesthesia and ethanol for maintenance of anesthesia. The direct effect of etomidate (1 and 5 micrograms/ml) and of its solvents on cardiac muscle was studied using rat left ventricular papillary muscle. Etomidate induced a slight positive inotropic effect in both solvents, as shown by an increase in maximum unloaded shortening velocity (Vmax) but not in force. At 0.5 mM Ca++ 5 micrograms/ml etomidate increased Vmax (128 +/- 18%, P less than 0.05) but not force (103 +/- 16%, NS). Using various afterloaded twitches, the peak power output (Emax) was calculated: 1 and 5 micrograms/ml etomidate increased Emax (107 +/- 8%, P less than 0.05, and 108 +/- 10%, P less than 0.05, respectively). This increase was related to the increase in Vmax and not in isometric force. Etomidate did not modify the elastic components of papillary muscle, isometric relaxation, and contraction-relaxation coupling under high load. Several findings suggest that etomidate in propylene glycol impaired the sarcoplasmic reticulum (SR) function: 1) it impaired the isotonic relaxation, the contraction-relaxation coupling under low load, and the load sensitivity of relaxation; and 2) it decreased postrest potentiated contraction, which is highly dependent on the SR. Nevertheless, alteration of SR function was only significant at high [Ca++]o and the beat-to-beat postrest recovery was not modified, indicating that the deleterious effects on SR function were moderate. The isotonic relaxation (max Vr) was more impaired by etomidate in propylene glycol (78 +/- 9%, P less than 0.001) and by propylene glycol alone (69 +/- 9%, P less than 0.001) than by etomidate in ethanol (97 +/- 12%, NS) and by ethanol alone (92 +/- 8%, P less than 0.05). This suggests that propylene glycol was responsible for the decrease in SR function. Etomidate in propylene glycol thus has a dual action on rat myocardium: 1) a slight positive inotropic effect due to etomidate per se, and 2) a slight decrease in SR function probably related to propylene glycol. However, because etomidate in propylene glycol induced a slight decrease in isometric force under certain experimental conditions (i.e., after isometric stabilization), etomidate in propylene glycol may induce a slight negative inotropic effect in some clinical conditions as a result of its dual action on the myocardium.

Animals↗
PubMed2003

Activation of alpha 2B-adrenoceptors mediates the cardiovascular effects of etomidate.

BACKGROUND: The intravenous anesthetic etomidate exhibits structural similarities to specific alpha2-adrenoceptor agonists of the type such as dexmedetomidine. The current study was performed to elucidate the possible interaction of etomidate with alpha2-adrenoceptors in mice lacking individual alpha2-adrenoceptor subtypes (alpha2-KO). METHODS: Sedative and cardiovascular responses to etomidate and the alpha2-agonist, dexmedetomidine, were determined in mice deficient in alpha2-receptor subtypes. Inhibition of binding of the alpha2-receptor antagonist [3H]RX821002 to recombinant alpha2-receptors by etomidate was tested in human embryonic kidney (HEK293) cells in vitro. RESULTS: In vivo, loss and recovery of the righting reflex required similar times after intraperitoneal injection of etomidate in wild-type and in alpha2A-receptor-deficient mice, indicating that the hypnotic effect of etomidate in mice does not require the alpha2A-receptor subtype. Intravenous injection of etomidate resulted in a transient increase (duration 2.4 +/- 0.2 min) in arterial blood pressure in wild-type mice (17 +/- 3 mmHg). Etomidate did not affect blood pressure in alpha2B-KO or alpha2AB-KO mice. In membranes from HEK293 cells transfected with alpha2-receptors, etomidate inhibited binding of the alpha2-antagonist, [3H]RX821002, with higher potency from alpha2B- and alpha2C-receptors than from alpha2A-receptors (Ki alpha2A 208 microm, alpha2B 26 microm, alpha2C 56 microm). In alpha2B-receptor-expressing HEK293 cells, etomidate rapidly increased phosphorylation of the extracellular signal-related kinases ERK1/2. CONCLUSIONS: These results indicate that etomidate acts as an agonist at alpha2-adrenoceptors, which appears in vivo primarily as an alpha2B-receptor-mediated increase in blood pressure. This effect of etomidate may contribute to the cardiovascular stability of patients after induction of anesthesia with etomidate.

Animals↗
PubMed1998

Vascular effects of etomidate administered for electroencephalographic burst suppression in humans.

Although its status as a neuroprotectant is controversial, etomidate is often employed for pharmacologic cerebral protection in aneurysm surgery. One purported advantage of etomidate over thiopental is its hemodynamic stability. This study examined the cardiovascular effects of etomidate given for electroencephalographic (EEG) burst suppression during cerebral aneurysm clipping in humans and the direct effects of etomidate on arteries in vitro. The charts of intracranial aneurysm surgery patients were retrospectively reviewed to determine the dose of etomidate employed, the frequency of concurrent vaspressor administration, and whether hemodynamic changes were associated with etomidate use. Against a background of balanced anesthesia, the dose of etomidate to induce burst suppression was 0.73 +/- 0.49 mg/kg (mean +/- SD) and the maintenance dose was 48 +/- 30 microg/kg/min. Etomidate produced an immediate decrease in mean arterial pressure that was sustained in patients who did not receive vasopressor support. During etomidate administration, 48% of patients (10 of 21) received some form of vasopressor support such as phenylephrine or ephedrine, and 62% of patients (13 of 21) receiving isoflurane had the anesthetic discontinued or its inspired concentration decreased. Etomidate in vitro produced dose-dependent relaxation of human internal mammary arterial rings that had been preconstricted by potassium or norepinephrine. Etomidate, in EEG burst suppression doses, decreases mean arterial pressure in anesthetized patients undergoing cerebral aneurysm surgery. One mechanism of etomidate-induced hypotension may be direct relaxation of vascular smooth muscle, because etomidate directly dilates preconstricted human arteries in vitro.

Adult↗
PubMed1989

Effect of time and dose on scalp-recorded somatosensory evoked potential wave augmentation by etomidate.

Bolus etomidate transiently increases the amplitude of scalprecorded somatosensory evoked potentials (SSEPs). The reproducibility of this augmentation and its dose-response relationship are unknown. In unpremedicated patients, we studied the effect on the SSEP of repetitive administration of single doses of etomidate (0.1 mg/kg i.v. bolus) in six patients and increasing doses of etomidate in six additional patients. Anesthesia was induced with fentanyl (15-20 microg/kg i.v.) plus thiopental (1-2 mg/kg i.v.) and maintannined with 0.4-0.8% isoflurane in oxygen, and the surgical incision was infiltrated with bupivicaine (0.5% without epinephrine). Etomidate administration was delayed for 30 min following anesthesia induction. In group 1, 0.1 mg/kg etomidate was administered intravenously as a bolus three times at 30-min intervals. In group 2, 0.05, 0.1, or 0.2 mg/kg was administered at 30-min intervals in random order in each patient. SSEPs were measured immediately before and once each minute for 5 min after etomidate administration following nondominant median nerve stimulation. In group 1, administration of 0.1 mg/kg etomidate (three trials) increased latency of an early negative wave (N20; latency approximately 20 ms) and a positive wave following N20 (P23; latency approximately 23 ms) by 1.0-1.4 and 1.3-2.6 ms, respectively (p < 0.05). P15N20 amplitude was increased by approximately 50% (range 36-76%; p < 0.05) and N20P23 amplitude was increased to 174% of control (range 173-178%; p < 0.05) and the amplitude increase was similar during the three etomidate administrations for both P15N20 and N20P23. Latency remained elevated by approximately 1.5 ms and amplitude remained elevated (P15N20 = 138%; N20P23 = 150%) 5 min following injection. Mean arterial blood pressure was unchanged by 0.1 mg/kg etomidate. In group 2, 0.05 mg/kg etomidate altered neither amplitude nor latency. However, 0.1 and 0.2 mg/kg increased N20P23 amplitude to 161 +/- 33 and 230 +/- 10% of control (p < 0.05), respectively. N20 and P23 latency were increased by 0.1 mg/kg etomidate by approximately 1.0 ms, while 0.2 mg/kg increased N20 latency by 1.0 ms and P23 latency by 1.5 ms. Bolus administration of etomidate (0.1 mg/kg) reproducibly increased SSEP amplitude and a larger dose (0.2 mg/kg) further increased amplitude augmentation. Thus, intermittent injection of etomidate can be used to augment small SSEP waves with reproducible increases in wave amplitude.

Journal Article↗
PubMed1993

Mechanism of the direct, negative inotropic effect of etomidate in isolated ferret ventricular myocardium.

BACKGROUND: Etomidate exerts a mild, positive inotropic effect in rat ventricular myocardium, yet has a negative inotropic effect in isolated rabbit ventricular myocardium. The aim of this study was to investigate the mechanisms of etomidate's inotropic effect and its underlying mechanism in isolated ferret ventricular myocardium (which shows similar physiologic characteristics as human ventricular myocardium) and in frog ventricular myocardium, in which Ca++ ions for myofibrillar activation are derived almost entirely from transsarcolemmal influx. METHODS: The authors analyzed the effects of etomidate after beta-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca++ transient detected with the Ca+(+)-regulated photoprotein aequorin. Etomidate's effects were also evaluated in ferret right ventricular papillary muscles in which the sarcoplasmic reticulum (SR) function was impaired by ryanodine, and in frog ventricular strips with little or no SR function. RESULTS: At concentrations > or = 3 micrograms/ml, which by far exceed the clinically useful concentration range, etomidate decreased contractility and the amplitude of the intracellular Ca++ transient. At equal peak force, control peak aequorin luminescence in [Ca++]o = 2.25 mM and peak aequorin luminescence in etomidate 10 micrograms/ml and [Ca++]o > 2.25 mM did not differ, which indicates that etomidate does not alter myofibrillar Ca++ sensitivity. After inactivation of sarcoplasmic reticulum Ca++ release with ryanodine 10(-6) M, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca++ influx, etomidate caused a decrease in contractility and in the amplitude of the intracellular Ca++ transient, and etomidate's relative negative inotropic effect was not different from that in control muscles not exposed to ryanodine. Etomidate 10 micrograms/ml decreased contractility in frog ventricular myocardium. CONCLUSIONS: These findings indicate that the direct negative inotropic effect of etomidate results from a decrease in intracellular Ca++ availability with no changes in myofibrillar Ca++ sensitivity. At least part of etomidate's action is caused by inhibition of transsarcolemmal Ca++ influx. Yet, these effects become apparent only at concentrations that are at least one order of magnitude larger than those encountered in clinical practice.

Animals↗