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PloS One 2018To investigate the effects of etomidate, emulsified isoflurane, and their combination with dexmedetomidine on physiological parameters, electrocardiogram (ECG) results,...
To investigate the effects of etomidate, emulsified isoflurane, and their combination with dexmedetomidine on physiological parameters, electrocardiogram (ECG) results, and the quality of induction and recovery during isoflurane maintenance anaesthesia. 5 mixed-breed dogs received each of four treatments: etomidate (E group); emulsified isoflurane (EI group); both dexmedetomidine and etomidate (DE group); or both dexmedetomidine and emulsified isoflurane (DEI group). All drugs were IV injection administered for induction, followed by 1.5 MAC (minimal alveolar concentration) of isoflurane to maintain anaesthesia. Rectal temperature (RT), respiratory rate (RR), heart rate (HR), mean arterial pressure (MAP), and ECG were measured at baseline, 0, 5, 10, 20, 40, and 60 minutes after intubation. The quality of induction and recovery was evaluated for all dogs. All the anaesthetic procedures provided good conditions for induction of anaesthesia. The quality of induction and recovery in the E group was worse than other groups. The decrease of RR in the E and DE groups was stronger than that in the EI and DEI groups. The dogs in the E group had the most significant prolongation of the Q-T interval and changes in the S-T segment. Deviation and extension of the S-T segment were noted in the El group. The dogs in the DE and DEI groups had fewer changes in the ECG results than those in the E and EI groups. The addition of dexmedetomidine caused less effect on cardiopulmonary parameters and the ECG results than either etomidate or emulsified isoflurane alone. Thus, etomidate or emulsified isoflurane in combination with dexmedetomidine may be useful clinically for the induction of anaesthesia.
Topics: Anesthetics, Inhalation; Animals; Arterial Pressure; Body Temperature; Dexmedetomidine; Dogs; Drug Interactions; Electrocardiography; Emulsions; Etomidate; Heart; Heart Rate; Isoflurane; Respiratory Physiological Phenomena; Respiratory Rate; Respiratory System; Time Factors
PubMed: 30532170
DOI: 10.1371/journal.pone.0208625 -
Annals of Emergency Medicine Jan 2017Induction doses of etomidate during rapid sequence intubation cause transient adrenal dysfunction, but its clinical significance on trauma patients is uncertain.... (Comparative Study)
Comparative Study
STUDY OBJECTIVE
Induction doses of etomidate during rapid sequence intubation cause transient adrenal dysfunction, but its clinical significance on trauma patients is uncertain. Ketamine has emerged as an alternative for rapid sequence intubation induction. Among adult trauma patients intubated in the emergency department, we compare clinical outcomes among those induced with etomidate and ketamine.
METHODS
The study entailed a retrospective evaluation of a 4-year (January 2011 to December 2014) period spanning an institutional protocol switch from etomidate to ketamine as the standard induction agent for adult trauma patients undergoing rapid sequence intubation in the emergency department of an academic Level I trauma center. The primary outcome was hospital mortality evaluated with multivariable logistic regression, adjusted for age, vital signs, and injury severity and mechanism. Secondary outcomes included ICU-free days and ventilator-free days evaluated with multivariable ordered logistic regression using the same covariates.
RESULTS
The analysis included 968 patients, including 526 with etomidate and 442 with ketamine. Hospital mortality was 20.4% among patients induced with ketamine compared with 17.3% among those induced with etomidate (adjusted odds ratio [OR] 1.41; 95% confidence interval [CI] 0.92 to 2.16). Patients induced with ketamine had ICU-free days (adjusted OR 0.80; 95% CI 0.63 to 1.00) and ventilator-free days (adjusted OR 0.96; 95% CI 0.76 to 1.20) similar to those of patients induced with etomidate.
CONCLUSION
In this analysis spanning an institutional protocol switch from etomidate to ketamine as the standard rapid sequence intubation induction agent for adult trauma patients, patient-centered outcomes were similar for patients who received etomidate and ketamine.
Topics: Adult; Conscious Sedation; Etomidate; Female; Hospital Mortality; Humans; Hypnotics and Sedatives; Intubation, Intratracheal; Ketamine; Male; Middle Aged; Retrospective Studies; Trauma Centers; Wounds and Injuries
PubMed: 27993308
DOI: 10.1016/j.annemergmed.2016.08.009 -
British Journal of Pharmacology Jun 1983In spontaneously breathing rats, continuous infusion of etomidate with and without fentanyl caused a slight decrease in blood pressure and heart rate. Coadministration... (Comparative Study)
Comparative Study
In spontaneously breathing rats, continuous infusion of etomidate with and without fentanyl caused a slight decrease in blood pressure and heart rate. Coadministration of fentanyl and etomidate in order to obtain full anaesthesia and analgesia resulted in respiratory depression. In artificially ventilated rats both etomidate as well as the anaesthetic combination caused a strong reduction in aortic flow and an increase in total peripheral resistance. A single infusion of etomidate did not change blood pressure. Etomidate combined with fentanyl reduced blood pressure. Under adjusted ventilation blood pressure, aortic flow, max(dF/dt) and heart rate were progressively reduced during a 4 h period. In contrast, urethane anaesthesia reduced aortic flow to a minor extent. Total peripheral resistance and max(dF/dt) were hardly affected. The slightly reduced blood pressure and blood gas variables remained stable during the experiment. From pharmacokinetic studies it was established that effective etomidate plasma levels were maintained constant during the experimental period. Pharmacokinetic interaction between etomidate and fentanyl did not occur. It is concluded that for anaesthesia of longer duration during cardiovascular experiments in rats, urethane is preferable to etomidate/fentanyl because it does not cause serious changes in basal haemodynamic variables.
Topics: Anesthesia; Animals; Blood Gas Analysis; Blood Pressure; Etomidate; Fentanyl; Heart Rate; Imidazoles; Male; Rats; Rats, Inbred Strains; Urethane
PubMed: 6652337
DOI: 10.1111/j.1476-5381.1983.tb11019.x -
Canadian Journal of Anaesthesia =... Feb 2011The purpose of this review is to summarize current knowledge of detailed biochemical evidence for the role of γ-aminobutyric acid type A receptors (GABA(A)-Rs) in the... (Review)
Review
PURPOSE
The purpose of this review is to summarize current knowledge of detailed biochemical evidence for the role of γ-aminobutyric acid type A receptors (GABA(A)-Rs) in the mechanisms of general anesthesia.
PRINCIPAL FINDINGS
With the knowledge that all general anesthetics positively modulate GABA(A)-R-mediated inhibitory transmission, site-directed mutagenesis comparing sequences of GABA(A)-R subunits of varying sensitivity led to identification of amino acid residues in the transmembrane domain that are critical for the drug actions in vitro. Using a photo incorporable analogue of the general anesthetic, R(+)etomidate, we identified two transmembrane amino acids that were affinity labelled in purified bovine brain GABA(A)-R. Homology protein structural modelling positions these two residues, αM1-11' and βM3-4', close to each other in a single type of intersubunit etomidate binding pocket at the β/α interface. This position would be appropriate for modulation of agonist channel gating. Overall, available information suggests that these two etomidate binding residues are allosterically coupled to sites of action of steroids, barbiturates, volatile agents, and propofol, but not alcohols. Residue α/βM2-15' is probably not a binding site but allosterically coupled to action of volatile agents, alcohols, and intravenous agents, and α/βM1-(-2') is coupled to action of intravenous agents.
CONCLUSIONS
Establishment of a coherent and consistent structural model of the GABA(A)-R lends support to the conclusion that general anesthetics can modulate function by binding to appropriate domains on the protein. Genetic engineering of mice with mutation in some of these GABA(A)-R residues are insensitive to general anesthetics in vivo, suggesting that further analysis of these domains could lead to development of more potent and specific drugs.
Topics: Allosteric Regulation; Anesthetics, General; Animals; Binding Sites; Cattle; Etomidate; Genetic Engineering; Humans; Mice; Models, Biological; Protein Binding; Receptors, GABA-A
PubMed: 21194017
DOI: 10.1007/s12630-010-9429-7 -
British Journal of Anaesthesia Dec 1992We have measured concentrations of etomidate and thiopentone in maternal plasma, umbilical venous plasma and colostrum after induction of anaesthesia in 40 patients...
We have measured concentrations of etomidate and thiopentone in maternal plasma, umbilical venous plasma and colostrum after induction of anaesthesia in 40 patients undergoing Caesarean section. Mean plasma etomidate concentration declined rapidly (1242.0 ng ml-1 at 5 min, 434.0 ng ml-1 at 15 min, 64.2 ng ml-1 at 30 min, 7.0 ng ml-1 at 60 min and undetectable 2 h after the injection). Mean plasma concentrations of thiopentone declined more slowly (6.09 micrograms ml-1 at 5 min, 2.64 micrograms ml-1 at 2 h, 1.35 micrograms ml-1 at 4 h, 0.86 microgram ml-1 at 9 h and 0.59 micrograms ml-1 at 12 h). Mean umbilical venous thiopentone concentration was 4.72 micrograms ml-1, whereas the thiopentone concentration in the maternal sample at 5 min was 6.09 micrograms ml-1, giving an umbilical:maternal vein ratio of 1:1.3. Mean umbilical etomidate concentration was 51.7 ng ml-1 and the corresponding maternal vein sample (5 min) was 1242.0 ng ml-1 (P < 0.001), giving an umbilical:maternal vein ratio of 1:24. Mean concentrations of thiopentone in colostrum were 1.98 micrograms ml-1 at 30 min, 0.91 microgram ml-1 at 4 h and 0.59 microgram ml-1 at 9 h, colostrum:plasma ratios at 4 h and 9 h being 0.67 and 0.68, respectively. Mean concentrations of etomidate in colostrum were 79.3 ng ml-1 at 30 min and 16.3 ng ml-1 at 2 h, being undetectable at 4 h. The colostrum:plasma etomidate concentration ratio was 1.2 at 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adult; Anesthesia, Intravenous; Anesthesia, Obstetrical; Cesarean Section; Colostrum; Etomidate; Female; Fetal Blood; Humans; Pregnancy; Thiopental
PubMed: 1467101
DOI: 10.1093/bja/69.6.586 -
Anesthesiology Nov 2022Etomidate, barbiturates, alfaxalone, and propofol are anesthetics that allosterically modulate γ-aminobutyric acid type A (GABAA) receptors via distinct sets of...
BACKGROUND
Etomidate, barbiturates, alfaxalone, and propofol are anesthetics that allosterically modulate γ-aminobutyric acid type A (GABAA) receptors via distinct sets of molecular binding sites. Two-state concerted coagonist models account for anesthetic effects and predict supra-additive interactions between drug pairs acting at distinct sites. Some behavioral and molecular studies support these predictions, while other findings suggest potentially complex anesthetic interactions. We therefore evaluated interactions among four anesthetics in both animals and GABAA receptors.
METHODS
The authors used video assessment of photomotor responses in zebrafish larvae and isobolography to evaluate hypnotic drug pair interactions. Voltage clamp electrophysiology and allosteric shift analysis evaluated coagonist interactions in α1β3γ2L receptors activated by γ-aminobutyric acid (GABA) versus anesthetics [log(d, AN):log(d, GABA) ratio]. Anesthetic interactions at concentrations relevant to zebrafish were assessed in receptors activated with low GABA.
RESULTS
In zebrafish larvae, etomidate interacted additively with both propofol and the barbiturate R-5-allyl-1-methyl m-trifluoromethyl mephobarbital (R-mTFD-MPAB; mean ± SD α = 1.0 ± 0.07 and 0.96 ± 0.11 respectively, where 1.0 indicates additivity), while the four other drug pairs displayed synergy (mean α range 0.76 to 0.89). Electrophysiologic allosteric shifts revealed that both propofol and R-mTFD-MPAB modulated etomidate-activated receptors much less than GABA-activated receptors [log(d, AN):log(d, GABA) ratios = 0.09 ± 0.021 and 0.38 ± 0.024, respectively], while alfaxalone comparably modulated receptors activated by GABA or etomidate [log(d) ratio = 0.87 ± 0.056]. With low GABA activation, etomidate combined with alfaxalone was supra-additive (n = 6; P = 0.023 by paired t test), but etomidate plus R-mTFD-MPAB or propofol was not.
CONCLUSIONS
In both zebrafish and GABAA receptors, anesthetic drug pairs interacted variably, ranging from additivity to synergy. Pairs including etomidate displayed corresponding interactions in animals and receptors. Some of these results challenge simple two-state coagonist models and support alternatives where different anesthetics may stabilize distinct receptor conformations, altering the effects of other drugs.
Topics: Animals; Etomidate; Zebrafish; Receptors, GABA; Mephobarbital; Receptors, GABA-A; Anesthetics; Propofol; Barbiturates; Binding Sites; Hypnotics and Sedatives; gamma-Aminobutyric Acid; Electrophysiology
PubMed: 36018576
DOI: 10.1097/ALN.0000000000004361 -
Drug Delivery Dec 2021The aim of this investigation was to develop an etomidate intravenous lipid emulsion (ETM-ILE) and evaluate its properties and . Etomidate (ETM) is a hydrophobic drug,...
The aim of this investigation was to develop an etomidate intravenous lipid emulsion (ETM-ILE) and evaluate its properties and . Etomidate (ETM) is a hydrophobic drug, and organic solvents must be added to an etomidate injectable solution (ETM-SOL) to aid dissolution, that causes various adverse reactions on injection. Lipid emulsions are a novel drug formulation that can improve drug loading and reduce adverse reactions. ETM-ILE was prepared using high-pressure homogenization. Univariate experiments were performed to select key conditions and variables. The proportion of oil, egg lecithin, and poloxamer 188 (F68) served as variables for the optimization of the ETM-ILE formulation by central composite design response surface methodology. The optimized formulation had the following characteristics: particle size, 168.0 ± 0.3 nm; polydispersity index, 0.108 ± 0.028; zeta potential, -36.4 ± 0.2 mV; drug loading, 2.00 ± 0.01 mg/mL; encapsulation efficiency, 97.65% ± 0.16%; osmotic pressure, 292 ± 2 mOsmol/kg and pH value, 7.63 ± 0.07. Transmission electron microscopy images showed that the particles were spherical or spheroidal, with a diameter of approximately 200 nm. The stability study suggested that ETM-ILE could store at 4 ± 2 °C or 25 ± 2 °C for 12 months. Safety tests showed that ETM-ILE did not cause hemolysis or serious vascular irritation. The results of the pharmacokinetic study found that ETM-ILE was bioequivalent to ETM-SOL. However, a higher concentration of ETM was attained in the liver, spleen, and lungs after administration of ETM-ILE than after administration of ETM-SOL. This study found that ETM-ILE had great potential for clinical applications.
Topics: Anesthetics, Intravenous; Animals; Chemistry, Pharmaceutical; Drug Stability; Etomidate; Fat Emulsions, Intravenous; Hydrogen-Ion Concentration; Lecithins; Male; Particle Size; Poloxamer; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Soybean Oil; Surface Properties
PubMed: 33960250
DOI: 10.1080/10717544.2021.1917729 -
Critical Care (London, England) 2006Etomidate is a potent suppressant of adrenal steroidogenesis,effectively inducing reversible pharmacological adrenalectomy. Recent evidence suggests that for every five... (Review)
Review
Etomidate is a potent suppressant of adrenal steroidogenesis,effectively inducing reversible pharmacological adrenalectomy. Recent evidence suggests that for every five patients with septic shock given etomidate without corticosteroid supplementation, one patient will die as a consequence. Other critically ill patients are also at possible risk, and this risk requires further exploration. Etomidate will also confound investigations into the effects of disease states on adrenal function, and should therefore be avoided. A moratorium on the use of etomidate in critically ill patients outside clinical trials may be prudent until its safety is established.
Topics: Adrenal Cortex Function Tests; Critical Illness; Etomidate; Humans
PubMed: 16941756
DOI: 10.1186/cc5020 -
Anaesthesia Feb 2006
Topics: Anesthetics, Intravenous; Electroconvulsive Therapy; Etomidate; Humans; Immune Tolerance
PubMed: 16430578
DOI: 10.1111/j.1365-2044.2005.04519_1.x -
BMC Pharmacology & Toxicology Aug 2019Cushing's syndrome is an endocrine disorder characterized by the overproduction of adrenocortical steroids. Steroidogenesis enzyme inhibitors are the mainstays of...
BACKGROUND
Cushing's syndrome is an endocrine disorder characterized by the overproduction of adrenocortical steroids. Steroidogenesis enzyme inhibitors are the mainstays of pharmacological treatment. Unfortunately, they produce significant side effects. Among the most potent inhibitors is the general anesthetic etomidate whose GABA receptor-mediated sedative-hypnotic actions restrict use. In this study, we defined the sedative-hypnotic and steroidogenesis inhibiting actions of etomidate and four phenyl-ring substituted etomidate analogs (dimethoxy-etomidate, isopropoxy-etomidate, naphthalene-etomidate, and naphthalene (2)-etomidate) that possess negligible GABA receptor modulatory activities.
METHODS
In the first set of experiments, male Sprague-Dawley rats were assessed for loss of righting reflexes (LoRR) after receiving intravenous boluses of either etomidate (1 mg/kg) or an etomidate analog (40 mg/kg). In the second set of experiments, rats were assessed for LoRR and their abilities to produce adrenocortical and androgenic steroids after receiving 2-h infusions (0.5 mg kg min) of either etomidate or an etomidate analog.
RESULTS
All rats that received etomidate boluses or infusions had LoRR that persisted for minutes or hours, respectively. In contrast, no rat that received an etomidate analog had LoRR. Compared to rats in the vehicle control group, rats that received etomidate analog infusions had plasma corticosterone and aldosterone concentrations that were reduced by 80-84% and 68-94%, respectively. Rats that received etomidate infusions had plasma corticosterone and aldosterone concentrations that were also significantly reduced (by 92 and 96%, respectively). Rats that received etomidate or isopropoxy-etomidate had significant reductions (90 and 57%, respectively) in plasma testosterone concentrations whereas those that received naphthalene-etomidate had significant increases (1400%) in plasma dehydroepiandrosterone concentrations. Neither etomidate nor any etomidate analog significantly affected plasma androstenedione and dihydrotestosterone concentrations.
CONCLUSIONS
Our studies demonstrate that the four phenyl-ring substituted etomidate analogs form a novel class of compounds that are devoid of sedative-hypnotic activities and suppress plasma concentrations of adrenocortical steroids but vary in their effects on plasma concentrations of androgenic steroids.
Topics: Animals; Etomidate; Hypnotics and Sedatives; Male; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Reflex; Steroid Synthesis Inhibitors; Steroids
PubMed: 31383012
DOI: 10.1186/s40360-019-0328-4