Review

Authors: Beatrijs I Valk, Michel M R F Struys

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

Review

Authors: Brian L Erstad, Jeffrey F Barletta

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

Meta-Analysis

Authors: Takatoshi Koroki, Yuki Kotani, Takahiko Yaguchi...

BACKGROUND

Tracheal intubation is a high-risk intervention commonly performed in critically ill patients. Due to its favorable cardiovascular profile, ketamine is considered less likely to compromise clinical outcomes. This meta-analysis aimed to assess whether ketamine, compared with other agents, reduces mortality in critically ill patients undergoing intubation.

METHODS

We searched MEDLINE, Embase, and the Cochrane Library from inception until April 27, 2023, for randomized controlled trials and matched observational studies comparing ketamine with any control in critically ill patients as an induction agent. The primary outcome was mortality at the longest follow-up available, and the secondary outcomes included Sequential Organ Failure Assessment score, ventilator-free days at day 28, vasopressor-free days at day 28, post-induction mean arterial pressure, and successful intubation on the first attempt. For the primary outcome, we used a Bayesian random-effects meta-analysis on the risk ratio (RR) scale with a weakly informative neutral prior corresponding to a mean estimate of no difference with 95% probability; the estimated effect size will fall between a relative risk of 0.25 and 4. The RR and 95% credible interval (CrI) were used to estimate the probability of mortality reduction (RR < 1). The secondary outcomes were assessed with a frequentist random-effects model. We registered this study in Open Science Framework ( https://osf.io/2vf79/ ).

RESULTS

We included seven randomized trials and one propensity-matched study totaling 2978 patients. Etomidate was the comparator in all the identified studies. The probability that ketamine reduced mortality was 83.2% (376/1475 [25%] vs. 411/1503 [27%]; RR, 0.93; 95% CrI, 0.79-1.08), which was confirmed by a subgroup analysis excluding studies with a high risk of bias. No significant difference was observed in any secondary outcomes.

CONCLUSIONS

All of the included studies evaluated ketamine versus etomidate among critically ill adults requiring tracheal intubation. This meta-analysis showed a moderate probability that induction with ketamine is associated with a reduced risk of mortality.

Topics: Ketamine; Humans; Etomidate; Intubation, Intratracheal; Critical Illness; Bayes Theorem

PubMed: 38368326
DOI: 10.1186/s13054-024-04831-4

Randomized Controlled Trial

Authors: Winchana Srivilaithon, Atidtaya Bumrungphanithaworn, Kiattichai Daorattanachai...

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

Authors: Weronika Chojnacka, Jinfeng Teng, Jeong Joo Kim...

Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in the 1960s-80s. Due to its high abuse potential, medical use of methaqualone was eventually prohibited, yet it persists as a globally abused substance. Methaqualone principally targets GABA receptors, which are the major inhibitory neurotransmitter-gated ion channels in the brain. The restricted status and limited accessibility of methaqualone have contributed to its pharmacology being understudied. Here, we use cryo-EM to localize the GABA receptor binding sites of methaqualone and its more potent derivative, PPTQ, to the same intersubunit transmembrane sites targeted by the general anesthetics propofol and etomidate. Both methaqualone and PPTQ insert more deeply into subunit interfaces than the previously-characterized modulators. Binding of quinazolinones to this site results in widening of the extracellular half of the ion-conducting pore, following a trend among positive allosteric modulators in destabilizing the hydrophobic activation gate in the pore as a mechanism for receptor potentiation. These insights shed light on the underexplored pharmacology of quinazolinones and further elucidate the molecular mechanisms of allosteric GABA receptor modulation through transmembrane binding sites.

Topics: Receptors, GABA-A; Binding Sites; Cryoelectron Microscopy; Humans; Animals; Etomidate; Propofol; Quinazolinones; Allosteric Regulation; HEK293 Cells; Hypnotics and Sedatives

PubMed: 38898000
DOI: 10.1038/s41467-024-49471-y

Randomized Controlled Trial

Authors: Ji Liu, Jinqiu Yang, Xiyang Yang...

BACKGROUND

Gastric cancer is the third most common malignant tumor with the second highest mortality rate in the world, and radical gastrectomy is the main treatment method, but the operation needs a long period of time to carry out and has strong surgical trauma stimulation, which is likely to cause sympathetic nerve excitement and stress reaction in the body. Therefore, the selection of appropriate anesthetic medication regimen and anesthesia method has an important impact on the intraoperative management and postoperative recovery of patients. This study aims to compare the clinical effects of dexmedetomidine alone in combination with propofol, etomidate and propofol-etomidate mixture in the treatment of radical gastrectomy for gastric cancer.

METHODS

A total of 90 patients undergoing elective radical gastrectomy were randomly divided into the propofol group (group P), the etomidate group (group E), and the etomidate-propofol mixture group (group PE). Anesthesia induction was performed under the monitoring of bispectral index anesthesia depth. The same pumping drugs were used in 3 groups: 0.1 to 0.3 μg/kg·min remifentanil, 0.5 μg/kg·h dexmedetomidine, and 5 to 10 μg/kg·min rocuronium. The primary outcome indicator was the hemodynamic conditions. The secondary outcome indicators included awakening time and time to accurately answer questions after operation, the prevalence of postoperative respiratory depression and adverse events, the incidence of postoperative cognitive dysfunction, and preoperative and postoperative Montreal Cognitive Assessment and Mini-Mental State Examination scores.

RESULTS

Among the 3 groups of patients, the use rate of vasoactive drugs in group P was higher (P < .05); the systolic blood pressure, diastolic blood pressure, and heart rate of group P at T1 to T4 were significantly lower than those of groups E and PE (P < .05); the systolic blood pressure, diastolic blood pressure, and heart rate of group E in T2, T4, and T6 were significantly higher than those of groups P and PE (P < .05). The wake-up time after operation and the time to accurately answer the questions were longer in group E than in groups P and PE (P < .05). The incidence of postoperative respiratory depression in group P was higher than that in groups E and PE (P < .05). The Montreal Cognitive Assessment score of group P was lower than that of groups E and PE 7 days after operation (P < .05).

CONCLUSION

Dexmedetomidine combined with propofol-etomidate mixture is a better anesthesia drug combination.

Topics: Humans; Dexmedetomidine; Propofol; Male; Female; Middle Aged; Gastrectomy; Etomidate; Anesthesia, General; Stomach Neoplasms; Anesthetics, Intravenous; Aged; Hypnotics and Sedatives; Adult

PubMed: 39496064
DOI: 10.1097/MD.0000000000039669

Authors: H Owen, A A Spence

Topics: Adrenal Cortex; Anesthesia, Intravenous; Etomidate; Humans; Imidazoles; Postoperative Complications

PubMed: 6721965
DOI: 10.1093/bja/56.6.555

Review

Authors: David J Merkler, Aidan J Hawley, Betty A Eipper...

Peptides play a key role in controlling many physiological and neurobiological pathways. Many bioactive peptides require a C-terminal α-amide for full activity. The bifunctional enzyme catalysing α-amidation, peptidylglycine α-amidating monooxygenase (PAM), is the sole enzyme responsible for amidated peptide biosynthesis, from Chlamydomonas reinhardtii to Homo sapiens. Many neuronal and endocrine functions are dependent upon amidated peptides; additional amidated peptides are growth promoters in tumours. The amidation reaction occurs in two steps, glycine α-hydroxylation followed by dealkylation to generate the α-amide product. Currently, most potentially useful inhibitors target the first reaction, which is rate-limiting. PAM is a membrane-bound enzyme that visits the cell surface during peptide secretion. PAM is then used again in the biosynthetic pathway, meaning that cell-impermeable inhibitors or inactivators could have therapeutic value for the treatment of cancer or psychiatric abnormalities. To date, inhibitor design has not fully exploited the structures and mechanistic details of PAM.

Topics: Amides; Animals; Biomarkers; Humans; Mixed Function Oxygenases; Molecular Targeted Therapy; Multienzyme Complexes; Peptides

PubMed: 35124797
DOI: 10.1111/bph.15815

Authors: Maria C Maldifassi, Erwin Sigel

Topics: Allosteric Site; Anesthetics; Animals; Binding Sites; DNA Mutational Analysis; Etomidate; Humans; Ions; Mutation; Neurotransmitter Agents; Oocytes; Pentobarbital; Propofol; Protein Domains; Protein Isoforms; Receptors, GABA-A; Xenopus

PubMed: 28099926
DOI: 10.18632/oncotarget.14616

Randomized Controlled Trial

Authors: Bailong Hu, Mei Zhang, Zhen Wu...

BACKGROUND

Remimazolam tosilate (RT) is a new ultrashort-acting γ-aminobutyric acid subtype A (GABA) agonist, with the characteristics of rapid onset and offset, minimal cardiorespiratory depression. Currently, few studies have compared the effect of RT and etomidate on hemodynamics during anesthesia induction. Here, we aimed to compare the hemodynamic effects of different doses of RT and etomidate for anesthesia induction in patients undergoing cardiac surgeries.

METHODS

Patients were recruited from January to September 2022 in this single-center, prospective, randomized, double-blind trial. A total of 117 patients undergoing selective valve replacement surgery were randomly divided into low-dose RT (0.2 mg/kg) group (group LR), high-dose RT (0.3 mg/kg) group (group HR), or etomidate (1.5 mg/kg) group (group E), respectively. The primary outcome was hemodynamic fluctuations (mean arterial pressure fluctuation value [∆MAP]; heart rate fluctuation value [∆HR]) during anesthesia induction. Secondary outcomes included the incidence of adverse drug reactions (injection pain and myoclonus) and adverse cardiovascular events, vital signs at different time points and the cumulative doses of vasoactive drugs.

RESULTS

The hemodynamic fluctuations (∆MAP) in group LR and group E were significantly lower than that in group HR. In addition, the incidence of hypotension and the cumulative norepinephrine doses in group E and group LR were also significantly lower than that in group HR. Furthermore, the incidence of injection pain and myoclonus in group LR and group HR were less frequently recorded compared with group E. There were no significant differences in terms of ∆HR, tachycardia, hypertension, severe bradycardia, vital signs at different time points, lactic acid and blood glucose between both groups.

CONCLUSION

Compared with etomidate, low-dose RT (0.2mg/kg) can not only provide stable hemodynamic parameters but also cause fewer adverse reactions when used for anesthesia induction in patients with cardiac disease.

Topics: Humans; Etomidate; Anesthetics, Intravenous; Myoclonus; Prospective Studies; Hemodynamics; Cardiac Surgical Procedures; Pain; Propofol

PubMed: 36789096
DOI: 10.2147/DDDT.S401969