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The American Journal of Emergency... Aug 2023Rapid-sequence intubation (RSI) is the process of administering a sedative and neuromuscular blocking agent (NMBA) in rapid succession to facilitate endotracheal... (Review)
Review
PURPOSE
Rapid-sequence intubation (RSI) is the process of administering a sedative and neuromuscular blocking agent (NMBA) in rapid succession to facilitate endotracheal intubation. It is the most common and preferred method for intubation of patients presenting to the emergency department (ED). The selection and use of medications to facilitate RSI is critical for success. The purpose of this review is to describe pharmacotherapies used during the RSI process, discuss current clinical controversies in RSI medication selection, and review pharmacotherapy considerations for alternative intubation methods.
SUMMARY
There are several steps to the intubation process requiring medication considerations, including pretreatment, induction, paralysis, and post-intubation sedation and analgesia. Pretreatment medications include atropine, lidocaine, and fentanyl; but use of these agents in clinical practice has fallen out of favor as there is limited evidence for their use outside of select clinical scenarios. There are several options for induction agents, though etomidate and ketamine are the most used due to their more favorable hemodynamic profiles. Currently there is retrospective evidence that etomidate may produce less hypotension than ketamine in patients presenting with shock or sepsis. Succinylcholine and rocuronium are the preferred neuromuscular blocking agents, and the literature suggests minimal differences between succinylcholine and high dose rocuronium in first-pass success rates. Selection between the two is based on patient specific factors, half-life and adverse effect profiles. Finally, medication-assisted preoxygenation and awake intubation are less common methods for intubation in the ED but require different considerations for medication use.
AREAS FOR FUTURE RESEARCH
The optimal selection, dosing, and administration of RSI medications is complicated, and further research is needed in several areas. Additional prospective studies are needed to determine optimal induction agent selection and dosing in patients presenting with shock or sepsis. Controversy exists over optimal medication administration order (paralytic first vs induction first) and medication dosing in obese patients, but there is insufficient evidence to significantly alter current practices regarding medication dosing and administration. Further research examining awareness with paralysis during RSI is needed before definitive and widespread practice changes to medication use during RSI can be made.
Topics: Humans; Succinylcholine; Etomidate; Rocuronium; Rapid Sequence Induction and Intubation; Ketamine; Retrospective Studies; Hypnotics and Sedatives; Emergency Service, Hospital; Neuromuscular Blocking Agents; Intubation, Intratracheal
PubMed: 37196592
DOI: 10.1016/j.ajem.2023.05.004 -
Journal of Critical Care Oct 2023We performed a meta-analysis of randomized controlled trials to evaluate if etomidate impacted mortality in critically ill adults when compared with other induction... (Meta-Analysis)
Meta-Analysis
PURPOSE
We performed a meta-analysis of randomized controlled trials to evaluate if etomidate impacted mortality in critically ill adults when compared with other induction agents.
MATERIALS AND METHODS
We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials which compared etomidate with any other induction agent in critically ill adult patients undergoing endotracheal intubation. The primary outcome was mortality at the main timepoint defined by the study. We conducted a fixed-effects meta-analysis for the risk ratio. Using that risk ratio and 95% confidence interval, we then estimated the probability of any harm (RR > 1) and the number needed to harm ≤100 (RR ≥ 1.05).
RESULTS
We included 11 randomized trials comprising 2704 patients. We found that etomidate increased mortality (319/1359 [23%] vs. 267/1345 [20%]; risk ratio (RR) = 1.16; 95% confidence interval (CI), 1.01-1.33; P = 0.03; I = 0%; number needed to harm = 31). The probabilities of any increase and a 1% increase (NNH ≤100) in mortality were 98.1% and 92.1%, respectively.
CONCLUSIONS
This meta-analysis found a high probability that etomidate increases mortality when used as an induction agent in critically ill patients with a number needed to harm of 31.
Topics: Adult; Humans; Etomidate; Critical Illness; Randomized Controlled Trials as Topic; Intubation, Intratracheal
PubMed: 37127020
DOI: 10.1016/j.jcrc.2023.154317 -
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 -
Intensive Care Medicine Jan 2022Etomidate and ketamine are hemodynamically stable induction agents often used to sedate critically ill patients during emergency endotracheal intubation. In 2015,... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Etomidate and ketamine are hemodynamically stable induction agents often used to sedate critically ill patients during emergency endotracheal intubation. In 2015, quality improvement data from our hospital suggested a survival benefit at Day 7 from avoidance of etomidate in critically ill patients during emergency intubation. In this clinical trial, we hypothesized that randomization to ketamine instead of etomidate would be associated with Day 7 survival after emergency endotracheal intubation.
METHODS
A prospective, randomized, open-label, parallel assignment, single-center clinical trial performed by an anesthesiology-based Airway Team under emergent circumstances at one high-volume medical center in the United States. 801 critically ill patients requiring emergency intubation were randomly assigned 1:1 by computer-generated, pre-randomized sealed envelopes to receive etomidate (0.2-0.3 mg/kg, n = 400) or ketamine (1-2 mg/kg, n = 401) for sedation prior to intubation. The pre-specified primary endpoint of the trial was Day 7 survival. Secondary endpoints included Day 28 survival.
RESULTS
Of the 801 enrolled patients, 396 were analyzed in the etomidate arm, and 395 in the ketamine arm. Day 7 survival was significantly lower in the etomidate arm than in the ketamine arm (77.3% versus 85.1%, difference - 7.8, 95% confidence interval - 13, - 2.4, p = 0.005). Day 28 survival rates for the two groups were not significantly different (etomidate 64.1%, ketamine 66.8%, difference - 2.7, 95% confidence interval - 9.3, 3.9, p = 0.294).
CONCLUSION
While the primary outcome of Day 7 survival was greater in patients randomized to ketamine, there was no significant difference in survival by Day 28.
Topics: Critical Illness; Etomidate; Humans; Intubation, Intratracheal; Ketamine; Prospective Studies
PubMed: 34904190
DOI: 10.1007/s00134-021-06577-x -
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 -
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 -
Sedative Dose for Rapid Sequence Intubation and Postintubation Hypotension: Is There an Association?Annals of Emergency Medicine Oct 2023For patients with hemodynamic instability undergoing rapid sequence intubation, experts recommend reducing the sedative medication dose to minimize the risk of further...
STUDY OBJECTIVE
For patients with hemodynamic instability undergoing rapid sequence intubation, experts recommend reducing the sedative medication dose to minimize the risk of further hemodynamic deterioration. Scant data support this practice for etomidate and ketamine. We sought to determine if the dose of etomidate or ketamine was independently associated with postintubation hypotension.
METHODS
We analyzed data from the National Emergency Airway Registry from January 2016 to December 2018. Patients aged 14 years or older were included if the first intubation attempt was facilitated with etomidate or ketamine. We used multivariable modeling to determine whether drug dose in milligrams per kilogram of patient weight was independently associated with postintubation hypotension (systolic blood pressure < 100 mm Hg).
RESULTS
We analyzed 12,175 intubation encounters facilitated by etomidate and 1,849 facilitated by ketamine. The median drug doses were 0.28 mg/kg (interquartile range [IQR] 0.22 mg/kg to 0.32 mg/kg) for etomidate and 1.33 mg/kg (IQR 1 mg/kg to 1.8 mg/kg) for ketamine. Postintubation hypotension occurred in 1,976 patients (16.2%) who received etomidate and in 537 patients (29.0%) who received ketamine. In multivariable models, neither the etomidate dose (adjusted odds ratio [aOR] 0.95, 95% confidence interval [CI] 0.90 to 1.01) nor ketamine dose (aOR 0.97, 95% CI 0.81 to 1.17) was associated with postintubation hypotension. Results were similar in sensitivity analyses excluding patients with preintubation hypotension and including only patients intubated for shock.
CONCLUSION
In this large registry of patients intubated after receiving either etomidate or ketamine, we observed no association between the weight-based sedative dose and postintubation hypotension.
Topics: Humans; Hypnotics and Sedatives; Etomidate; Rapid Sequence Induction and Intubation; Ketamine; Intubation, Intratracheal; Retrospective Studies; Hypotension
PubMed: 37389494
DOI: 10.1016/j.annemergmed.2023.05.014 -
Chemical Reviews Oct 2021In this contribution, we provide a comprehensive overview of acyclic twisted amides, covering the literature since 1993 (the year of the first recognized report on... (Review)
Review
In this contribution, we provide a comprehensive overview of acyclic twisted amides, covering the literature since 1993 (the year of the first recognized report on acyclic twisted amides) through June 2020. The review focuses on classes of acyclic twisted amides and their key structural properties, such as amide bond twist and nitrogen pyramidalization, which are primarily responsible for disrupting to π* conjugation. Through discussing acyclic twisted amides in comparison with the classic bridged lactams and conformationally restricted cyclic fused amides, the reader is provided with an overview of amidic distortion that results in novel conformational features of acyclic amides that can be exploited in various fields of chemistry ranging from organic synthesis and polymers to biochemistry and structural chemistry and the current position of acyclic twisted amides in modern chemistry.
Topics: Amides; Chemistry Techniques, Synthetic; Lactams; Molecular Conformation; Nitrogen
PubMed: 34406005
DOI: 10.1021/acs.chemrev.1c00225 -
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 -
Organic & Biomolecular Chemistry Oct 2018During the past century, β-lactams have been identified as the core of penicillin and since then several strategies have been developed for their synthesis. Traditional... (Review)
Review
During the past century, β-lactams have been identified as the core of penicillin and since then several strategies have been developed for their synthesis. Traditional methods for β-lactam synthesis usually involved amide bond formation and the Staudinger reaction. In recent years, by the advancement of photo- and transition metal-catalysis, several new methods have been reported for β-lactam synthesis. For instance: ligand assisted metal catalyzed C-H activation/intermolecular oxidative amidation draws attention for β-lactam synthesis. In this review we introduce methods for β-lactam synthesis and present newly developed reactions. We approach the synthesis of β-lactams according to different retro synthesis strategies.
Topics: Amides; Anti-Bacterial Agents; Catalysis; Chemistry Techniques, Synthetic; Metals; Methane; Oxidation-Reduction; Penicillins; beta-Lactams
PubMed: 30209477
DOI: 10.1039/c8ob01833b