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Clinical Pharmacokinetics Oct 2021Etomidate is a hypnotic agent that is used for the induction of anesthesia. It produces its effect by acting as a positive allosteric modulator on the γ-aminobutyric... (Review)
Review
Etomidate is a hypnotic agent that is used for the induction of anesthesia. It produces its effect by acting as a positive allosteric modulator on the γ-aminobutyric acid type A receptor and thus enhancing the effect of the inhibitory neurotransmitter γ-aminobutyric acid. Etomidate stands out among other anesthetic agents by having a remarkably stable cardiorespiratory profile, producing no cardiovascular or respiratory depression. However, etomidate suppresses the adrenocortical axis by the inhibition of the enzyme 11β-hydroxylase. This makes the drug unsuitable for administration by a prolonged infusion. It also makes the drug unsuitable for administration to critically ill patients. Etomidate has relatively large volumes of distributions and is rapidly metabolized by hepatic esterases into an inactive carboxylic acid through hydrolyzation. Because of the decrease in popularity of etomidate, few modern extensive pharmacokinetic or pharmacodynamic studies exist. Over the last decade, several analogs of etomidate have been developed, with the aim of retaining its stable cardiorespiratory profile, whilst eliminating its suppressive effect on the adrenocortical axis. One of these molecules, ABP-700, was studied in extensive phase I clinical trials. These found that ABP-700 is characterized by small volumes of distribution and rapid clearance. ABP-700 is metabolized similarly to etomidate, by hydrolyzation into an inactive carboxylic acid. Furthermore, ABP-700 showed a rapid onset and offset of clinical effect. One side effect observed with both etomidate and ABP-700 is the occurrence of involuntary muscle movements. The origin of these movements is unclear and warrants further research.
Topics: Anesthesia; Etomidate; Humans; Hypnotics and Sedatives
PubMed: 34060021
DOI: 10.1007/s40262-021-01038-6 -
JAMA Surgery Oct 2022Older patients may benefit from the hemodynamic stability of etomidate for general anesthesia. However, it remains uncertain whether the potential for adrenocortical...
IMPORTANCE
Older patients may benefit from the hemodynamic stability of etomidate for general anesthesia. However, it remains uncertain whether the potential for adrenocortical suppression with etomidate may increase morbidity.
OBJECTIVE
To test the primary hypothesis that etomidate vs propofol for anesthesia does not increase in-hospital morbidity after abdominal surgery in older patients.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter, parallel-group, noninferiority randomized clinical trial (Etomidate vs Propofol for In-hospital Complications [EPIC]) was conducted between August 15, 2017, and November 20, 2020, at 22 tertiary hospitals in China. Participants were aged 65 to 80 years and were scheduled for elective abdominal surgery. Patients and outcome assessors were blinded to group allocation. Data analysis followed a modified intention-to-treat principle.
INTERVENTIONS
Patients were randomized 1:1 to receive either etomidate or propofol for general anesthesia by target-controlled infusion.
MAIN OUTCOMES AND MEASURES
Primary outcome was a composite of major in-hospital postoperative complications (with a noninferiority margin of 3%). Secondary outcomes included intraoperative hemodynamic measurements; postoperative adrenocortical hormone levels; self-reported postoperative pain, nausea, and vomiting; and mortality at postoperative months 6 and 12.
RESULTS
A total of 1944 participants were randomized, of whom 1917 (98.6%) completed the trial. Patients were randomized to the etomidate group (n = 967; mean [SD] age, 70.3 [4.0] years; 578 men [59.8%]) or propofol group (n = 950; mean [SD] age, 70.6 [4.2] years; 533 men [56.1%]). The primary end point occurred in 90 of 967 patients (9.3%) in the etomidate group and 83 of 950 patients (8.7%) in the propofol group, which met the noninferiority criterion (risk difference [RD], 0.6%; 95% CI, -1.6% to 2.7%; P = .66). In the etomidate group, mean (SD) cortisol levels were lower at the end of surgery (4.8 [2.7] μg/dL vs 6.1 [3.4] μg/dL; P < .001), and mean (SD) aldosterone levels were lower at the end of surgery (0.13 [0.05] ng/dL vs 0.15 [0.07] ng/dL; P = .02) and on postoperative day 1 (0.14 [0.04] ng/dL vs 0.16 [0.06] ng/dL; P = .001) compared with the propofol group. No difference in mortality was observed between the etomidate and propofol groups at postoperative month 6 (2.2% vs 3.0%; RD, -0.8%; 95% CI, -2.2% to 0.7%) and 12 (3.3% vs 3.9%; RD, -0.6%; 95% CI, -2.3% to 1.0%). More patients had pneumonia in the etomidate group than in the propofol group (2.0% vs 0.3%; RD, 1.7%; 95% CI, 0.7% to 2.8%; P = .001). Results were consistent in the per-protocol population.
CONCLUSIONS AND RELEVANCE
Results of this trial showed that, compared with propofol, etomidate anesthesia did not increase overall major in-hospital morbidity after abdominal surgery in older patients, although it induced transient adrenocortical suppression.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02910206.
Topics: Aged; Aldosterone; Anesthesia, General; Anesthesia, Intravenous; Anesthetics, Intravenous; Etomidate; Hospitals; Humans; Hydrocortisone; Male; Postoperative Complications; Propofol
PubMed: 35947398
DOI: 10.1001/jamasurg.2022.3338 -
Critical Care (London, England) Jun 2020Practice guidelines provide clear evidence-based recommendations for the use of drug therapy to manage pain, agitation, and delirium associated with critical illness.... (Review)
Review
Practice guidelines provide clear evidence-based recommendations for the use of drug therapy to manage pain, agitation, and delirium associated with critical illness. Dosing recommendations however are often based on strategies used in patients with normal body habitus. Recommendations specific to critically ill patients with extreme obesity are lacking. Nonetheless, clinicians must craft dosing regimens for this population. This paper is intended to help clinicians design initial dosing regimens for medications commonly used in the management of pain, agitation, and delirium in critically ill patients with extreme obesity. A detailed literature search was conducted with an emphasis on obesity, pharmacokinetics, and dosing. Relevant manuscripts were reviewed and strategies for dosing are provided.
Topics: Analgesia; Analgesics, Non-Narcotic; Analgesics, Opioid; Benzodiazepines; Critical Illness; Deep Sedation; Delirium; Dexmedetomidine; Dose-Response Relationship, Drug; Etomidate; Haloperidol; Humans; Ketamine; Obesity; Pain Management; Quetiapine Fumarate
PubMed: 32513237
DOI: 10.1186/s13054-020-03040-z -
Scientific Reports Apr 2023Patients with sepsis often require emergency intubation. In emergency departments (EDs), rapid-sequence intubation with a single-dose induction agent is standard... (Randomized Controlled Trial)
Randomized Controlled Trial
Patients with sepsis often require emergency intubation. In emergency departments (EDs), rapid-sequence intubation with a single-dose induction agent is standard practice, but the best choice of induction agent in sepsis remains controversial. We conducted a randomized, controlled, single-blind trial in the ED. We included septic patients who were aged at least 18 years and required sedation for emergency intubation. Patients were randomly assigned by a blocked randomization to receive 0.2-0.3 mg/kg of etomidate or 1-2 mg/kg of ketamine for intubation. The objectives were to compare the survival outcomes and adverse events after intubation between etomidate and ketamine. Two hundred and sixty septic patients were enrolled; 130 patients/drug arm whose baseline characteristics were well balanced at baseline. In the etomidate group, 105 patients (80.8%) were alive at 28 days, compared with 95 patients (73.1%) in the ketamine group (risk difference [RD], 7.7%; 95% confidence interval [CI], - 2.5 to 17.9%; P = 0.092). There was no significant difference in the proportion of patients who survived at 24 h (91.5% vs. 96.2%; P = 0.097) and survived at 7 days (87.7% vs. 87.7%; P = 0.574). A significantly higher proportion of the etomidate group needed a vasopressor within 24 h after intubation: 43.9% vs. 17.7%, RD, 26.2% (95% CI, 15.4 to 36.9%; P < 0.001). In conclusion, there were no differences in early and late survival rates between etomidate and ketamine. However, etomidate was associated with higher risks of early vasopressor use after intubation. Trial registration: The trial protocol was registered in the Thai Clinical Trials Registry (identification number: TCTR20210213001). Registered 13 February 2021-Retrospectively registered, https://www.thaiclinicaltrials.org/export/pdf/TCTR20210213001 .
Topics: Humans; Adolescent; Adult; Etomidate; Ketamine; Anesthetics, Intravenous; Single-Blind Method; Intubation, Intratracheal; Sepsis; Emergency Service, Hospital; Vasoconstrictor Agents
PubMed: 37076524
DOI: 10.1038/s41598-023-33679-x -
Drug Design, Development and Therapy 2021The optimal sedation regime during endoscopy remains controversial, especially for elderly outpatients. In this study, we compared the efficacy and safety between... (Randomized Controlled Trial)
Randomized Controlled Trial
The Efficacy and Safety of Remimazolam Tosilate versus Etomidate-Propofol in Elderly Outpatients Undergoing Colonoscopy: A Prospective, Randomized, Single-Blind, Non-Inferiority Trial.
OBJECTIVE
The optimal sedation regime during endoscopy remains controversial, especially for elderly outpatients. In this study, we compared the efficacy and safety between remimazolam tosilate (RT) and etomidate-propofol (EP) in elderly outpatients undergoing colonoscopy.
METHODS
A total of 260 elderly outpatients undergoing sedative colonoscopy were randomized into two groups. Patients in the RT group received a 0.075-mg/kg maintenance dose of remimazolam following an initial dose of 0.15 mg/kg, whereas patients in the EP group (10 mL:20 mg etomidate plus 10 mL:100 mg propofol) received a 0.05-mL/kg maintenance dose following an initial dose of 0.1 mL/kg to maintain a Modified Observer's Assessment of Alertness/Sedation score of ≤3 during the procedure. The primary endpoint was the success of the procedure. Secondary endpoints included time metrics, hemodynamics, consumption of fentanyl, etomidate, propofol, and remimazolam, intraoperative body movement, patient and endoscopist satisfaction scores, supplemental dose of sedative and fentanyl, and incidence and severity of adverse events.
RESULTS
The procedure success rate was 96.52% in the RT group and 100% in the EP group. The difference in procedure success rate between the RT and EP groups was -3.48% (95% confidence interval: -6.81%, -0.15%). Four patients in the RT group required rescue midazolam. Compared with patients in the RT group, the onset time of the EP group was significantly lower ( < 0.05), whereas time to fully alert ( = 0.001), ready for discharge ( = 0.001), and hospital discharge ( = 0.002) were all significantly higher in the EP group. However, there were no significant differences in procedure time ( = 0.846) or cecal intubation time ( = 0.320) between the two groups. Although the frequency of intraoperative body movement was higher in the RT group, the difference was not significant ( = 0.508). There were no significant differences in patients' demographic and baseline characteristics, supplemental doses of sedative and fentanyl, or patient and endoscopist satisfaction scores ( > 0.05). Muscular tremor and pain on injection were recorded more frequently in the EP group ( < 0.05). However, there were no significant differences in hypoxia, respiratory depression, or incidence of postoperative nausea and vomiting. The severity of adverse events was all mild (grade 1) across both groups.
CONCLUSION
RT may have non-inferior efficacy and a higher safety profile than EP in elderly outpatients undergoing colonoscopy, which suggests that RT may be more suitable for elderly outpatients undergoing colonoscopy.
Topics: Aged; Benzodiazepines; Colonoscopy; Dose-Response Relationship, Drug; Etomidate; Female; Humans; Male; Muscle, Skeletal; Outpatients; Pain; Propofol; Prospective Studies; Single-Blind Method; Tremor
PubMed: 34819721
DOI: 10.2147/DDDT.S339535 -
Anesthesiology Mar 2011This review focuses on the unique clinical and molecular pharmacologic features of etomidate. Among general anesthesia induction drugs, etomidate is the only imidazole,... (Review)
Review
This review focuses on the unique clinical and molecular pharmacologic features of etomidate. Among general anesthesia induction drugs, etomidate is the only imidazole, and it has the most favorable therapeutic index for single-bolus administration. It also produces a unique toxicity among anesthetic drugs: inhibition of adrenal steroid synthesis that far outlasts its hypnotic action and that may reduce survival of critically ill patients. The major molecular targets mediating anesthetic effects of etomidate in the central nervous system are specific γ-aminobutyric acid type A receptor subtypes. Amino acids forming etomidate binding sites have been identified in transmembrane domains of these proteins. Etomidate binding site structure models for the main enzyme mediating etomidate adrenotoxicity have also been developed. Based on this deepening understanding of molecular targets and actions, new etomidate derivatives are being investigated as potentially improved sedative-hypnotics or for use as highly selective inhibitors of adrenal steroid synthesis.
Topics: Adrenal Cortex Hormones; Anesthesia, Intravenous; Anesthetics, Intravenous; Animals; Animals, Genetically Modified; Etomidate; Hemodynamics; Humans; Hypnotics and Sedatives; Mutation; Receptors, Adrenergic; Receptors, GABA-A; Steroids
PubMed: 21263301
DOI: 10.1097/ALN.0b013e3181ff72b5 -
Anesthesiology Nov 2016Etomidate potently suppresses adrenocortical steroid synthesis with potentially deleterious consequences by binding to 11β-hydroxylase and inhibiting its function. The...
BACKGROUND
Etomidate potently suppresses adrenocortical steroid synthesis with potentially deleterious consequences by binding to 11β-hydroxylase and inhibiting its function. The authors hypothesized that other sedative-hypnotics currently in clinical use or under development (or their metabolites) might bind to the same site at clinically relevant concentrations. The authors tested this hypothesis by defining etomidate's affinity for this site and the potencies with which other sedative-hypnotics (and their metabolites) inhibit etomidate binding.
METHODS
H-etomidate's binding to adrenal membranes from Sprague-Dawley rats was characterized with a filtration assay, and its dissociation constant was defined using saturation and homologous ligand competition approaches. Half-inhibitory concentrations of sedative-hypnotics and metabolites were determined from the reduction in specific H-etomidate binding measured in the presence of ranging sedative-hypnotic and metabolite concentrations.
RESULTS
Saturation and homologous competition studies yielded H-etomidate dissociation constants of 40 and 21 nM, respectively. Half-inhibitory concentrations of etomidate and cyclopropyl methoxycarbonyl metomidate (CPMM) differed significantly (26 vs. 143 nM, respectively; P < 0.001), and those of the carboxylic acid (CA) metabolites etomidate-CA and CPMM-CA were greater than or equal to 1,000× higher than their respective parent hypnotics. The half-inhibitory concentration of dexmedetomidine was 2.2 µM, whereas those of carboetomidate, ketamine, and propofol were greater than or equal to 50 µM.
CONCLUSION
Etomidate's in vitro dissociation constant for 11β-hydroxylase closely approximates its in vivo adrenocortical half-inhibitory concentration. CPMM produces less adrenocortical suppression than etomidate not only because it is metabolized faster but also because it binds to 11β-hydroxylase with lower affinity. Other sedative-hypnotics and metabolites bind to 11β-hydroxylase and inhibit etomidate binding only at suprahypnotic concentrations.
Topics: Adrenal Cortex; Anesthetics, Dissociative; Animals; Etomidate; Hypnotics and Sedatives; Ketamine; Models, Animal; Propofol; Pyrroles; Rats; Rats, Sprague-Dawley; Steroid 11-beta-Hydroxylase; Structure-Activity Relationship
PubMed: 27541316
DOI: 10.1097/ALN.0000000000001304 -
Nature Communications Jun 2023General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating...
General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and inhibiting excitatory ion channels, with the net effect of dampening nervous system excitability. Neuromuscular blockers act by antagonizing nicotinic acetylcholine receptors at the motor endplate; these excitatory ligand-gated ion channels are also inhibited by general anesthetics. The mechanisms by which anesthetics and neuromuscular blockers inhibit nicotinic receptors are poorly understood but underlie safe and effective surgeries. Here we took a direct structural approach to define how a commonly used anesthetic and two neuromuscular blockers act on a muscle-type nicotinic receptor. We discover that the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized-like state of the channel. The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state. Together, this study reveals a structural mechanism for how general anesthetics work on excitatory nicotinic receptors and further rationalizes clinical observations in how general anesthetics and neuromuscular blockers interact.
Topics: Humans; Receptors, Nicotinic; Anesthetics; Anesthetics, Intravenous; Anesthetics, General; Etomidate; Muscles
PubMed: 37264005
DOI: 10.1038/s41467-023-38827-5 -
Physiological Research Apr 2023Increased incidence of postoperative cognitive dysfunction (POCD) is observed in elderly patients underwent intravenous anesthesia (TIVA) with endotracheal intubation.... (Randomized Controlled Trial)
Randomized Controlled Trial
Increased incidence of postoperative cognitive dysfunction (POCD) is observed in elderly patients underwent intravenous anesthesia (TIVA) with endotracheal intubation. Modulation of anesthetics compatibility may reduce the severity of POCD. Elderly patients scheduled for TIVA with endotracheal intubation were randomly divided into the control group (1.00?2.00 mg/kg propofol) and the etomidate and propofol combination group (1.00?2.00 mg/kg propofol and 0.30 mg/kg etomidate). Serum cortisol, S100?, and neuron-specific enolase (NSE), interleukin (IL)-6, and IL-10 were monitored during or after the operation. Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were utilized to assess the severity of POCD. 63 elderly patients in the etomidate and propofol combination group and 60 patients in the control group were enrolled, and there was no significant difference in gender, American Society of Anesthesiologists (ASA) physical status, surgical specialty, intraoperative blood loss, and operation time between the two groups. Significantly increased serum cortisol, S100?, NSE, IL-6, and reduced MMSE and MoCA scores were detected in the control group at different time points after the operation (0-72 h post operation) when compared to those before the operation. Similar trends for these observed factors were found in the etomidate and propofol combination group. In addition, the etomidate and propofol combination group showed better effects in reducing the serum levels of cortisol, S100?, NSE, IL-6, and increasing the MMSE and MoCA scores when compared to the control group. The present study demonstrates that the combination of propofol with etomidate could alleviate POCD in elderly patients underwent TIVA with endotracheal intubation anesthesia.
Topics: Aged; Humans; Postoperative Cognitive Complications; Etomidate; Propofol; Anesthesia, Intravenous; Hydrocortisone; Interleukin-6; Anesthesia, General
PubMed: 37159858
DOI: 10.33549/physiolres.934983 -
In Vivo (Athens, Greece) 2022The influence of surgical interventions and anaesthesiological procedures on tumour progression was investigated as early as the 1920s. In current cancer management, the...
BACKGROUND/AIM
The influence of surgical interventions and anaesthesiological procedures on tumour progression was investigated as early as the 1920s. In current cancer management, the perioperative phase is increasingly being considered a vulnerable period with an increased risk of tumour cell dissemination due to medication, surgical manipulation, and immunosuppression. The extent to which narcotics administered in the perioperative setting influence the oncological outcomes of patients with pancreatic cancer is still unclear.
MATERIALS AND METHODS
To investigate the effect of propofol and etomidate on the proliferation, cell-cycle distribution, apoptosis, and necrosis of pancreatic tumour cells in vitro, PaTu 8988t and Panc-1 pancreatic cancer cells were treated with 0-1,000 μM propofol or etomidate for 24 h each. Cell proliferation was measured with enzyme-linked immunosorbent-bromodeoxyuridine assay. The apoptosis rate was analysed with annexin V staining and the cell-cycle distribution with flow cytometry.
RESULTS
Propofol at 1,000 μM induced apoptosis and inhibited cell proliferation. The cell cycle showed an increased S-phase and reduced cells in the G-phase. At 100 μM, propofol significantly inhibited proliferation of the pancreatic cancer cell line PaTu 8988t and reduced cells in the G-phase in the cell cycle. Etomidate had no effects on cell-cycle distribution, proliferation, apoptosis, and necrosis at the concentrations used.
CONCLUSION
In this study, propofol was shown to have anticancer effects by induction of apoptosis and inhibition of cell proliferation, while etomidate did not affect pancreatic cancer cells. However, it is too early to make any recommendation for changes in clinical practice and further clinical studies are warranted to investigate the effect of anaesthetics on cancer progression.
Topics: Humans; Etomidate; Propofol; Apoptosis; Necrosis; Pancreatic Neoplasms; Cell Cycle; Cell Proliferation
PubMed: 36309382
DOI: 10.21873/invivo.13008