Effects of etomidate combined with dexmedetomidine on adrenocortical function in elderly patients: a double-blind randomized controlled trial.

Etomidate has been advocated to be used in anesthesia for the elderly and the critically ill patients due to its faint effect on cardiovascular system. But the dose-dependent suppression of etomidate on adrenal cortex function leads to the limitation of its clinical application. Clinical research showed that dexmedetomidine could reduce the dose requirements for intravenous or inhalation anesthetics and opioids, and the hemodynamics was more stable during the operation. The objective was to observe the effect of etomidate combined with dexmedetomidine on adrenocortical function in elderly patients. 180 elderly patients scheduled for elective ureteroscopic holmium laser lithotripsy were randomly allocated to PR group anesthetized with propofol-remifentanil, ER group anesthetized with etomidate-remifentanil, and ERD group anesthetized with dexmedetomidine combined with etomidate-remifentanil. Patients in each group whose operation time was less than or equal to 1 h were incorporated into short time surgery group (PR1 group, ER1 group and ERD1 group), and whose surgical procedure time was more than 1 h were incorporated into long time surgery group (PR2 group, ER2 group and ERD2 group). The primary outcome was the serum cortisol and ACTH concentration. The secondary outcomes were the values of SBP, DBP, HR and SpO2, the time of surgical procedure, the dosage of etomidate and remifentanil administered during surgery, the time to spontaneous respiration, recovery and extubation, and the duration of stay in the PACU. The Serum cortisol concentration was higher at t1~2 in ERD1 group compared to ER1 group (P < 0.05). The Serum cortisol concentration at t1~3 was higher in ERD2 group than in ER2 group (P < 0.05). The Serum ACTH concentration was lower at t1~2 in ERD1 group compared to ER1 group (P < 0.05). The Serum ACTH concentration at t1~3 was lower in ERD2 group compared to ER2 group (P < 0.05). The SBP at T1 and T3 were higher in ER2 and ERD2 group than in PR2 group (P < 0.05). The DBP in ER1 and ERD1 group were higher at T1 compared to PR1 group (P < 0.05). The dosage of etomidate was significantly lower in ERD1 group and ERD2 group than in ER1 group and ER2 group (P < 0.05), respectively. The administration of dexmedetomidine combined with etomidate can attenuate the inhibition of etomidate on adrenocortical function in elderly patients and maintain intraoperative hemodynamic stability.

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 (p < 0.05), whereas time to fully alert (p = 0.001), ready for discharge (p = 0.001), and hospital discharge (p = 0.002) were all significantly higher in the EP group. However, there were no significant differences in procedure time (p = 0.846) or cecal intubation time (p = 0.320) between the two groups. Although the frequency of intraoperative body movement was higher in the RT group, the difference was not significant (p = 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 (p > 0.05). Muscular tremor and pain on injection were recorded more frequently in the EP group (p < 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.

Optimization, and in vitro and in vivo evaluation of etomidate intravenous lipid emulsion.

The aim of this investigation was to develop an etomidate intravenous lipid emulsion (ETM-ILE) and evaluate its properties in vitro and in vivo. 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.

Para-chloro-2-[18F]fluoroethyl-etomidate: A promising new PET radiotracer for adrenocortical imaging.

Introduction: [11C]Metomidate ([11C]MTO), the methyl ester analogue of etomidate, was developed as a positron emission tomography (PET) radiotracer for adrenocortical tumours and has also been suggested for imaging in primary aldosteronism (PA). A disadvantage of [11C]MTO is the rather high non-specific binding in the liver, which impacts both visualization and quantification of the uptake in the right adrenal gland. Furthermore, the short 20-minute half-life of carbon-11 is a logistic challenge in the clinical setting. Objectives: The aim of this study was to further evaluate the previously published fluorine-18 (T1/2=109.5 min) etomidate analogue, para-chloro-2-[18F]fluoroethyl etomidate; [18F]CETO, as an adrenal PET tracer. Methods: In vitro experiments included autoradiography on human and cynomolgus monkey (non-human primate, NHP) tissues and binding studies on adrenal tissue from NHPs. In vivo studies with [18F]CETO in mice, rats and NHP, using PET and CT/MRI, assessed biodistribution and binding specificity in comparison to [11C]MTO. Results: The binding of [18F]CETO in the normal adrenal cortex, as well as in human adrenocortical adenomas and adrenocortical carcinomas, was shown to be specific, both in vitro (in humans) and in vivo (in rats and NHP) with an in vitro Kd of 0.66 nM. Non-specific uptake of [18F]CETO in NHP liver was found to be low compared to that of [11C]MTO. Conclusions: High specificity of [18F]CETO to the adrenal cortex was demonstrated, with in vivo binding properties qualitatively surpassing those of [11C]MTO. Non-specific binding to the liver was significantly lower than that of [11C]MTO. [18F]CETO is a promising new PET tracer for imaging of adrenocortical disease and should be evaluated further in humans.

Factors associated with post-electroconvulsive therapy delirium: A retrospective chart review study.

ABSTRACT: Although electroconvulsive therapy (ECT) is generally a safe therapeutic method, unexpected adverse effects, such as post-ECT delirium, may occur. Despite its harmful consequences, there has been little discussion about the predictors of post-ECT delirium. Thus, the current study aimed to clarify the factors associated with post-ECT delirium by reviewing electronic medical records of 268 bitemporal ECT sessions from December 2006 to July 2018 in a university hospital.Demographic and clinical characteristics of sessions involving patients with or without post-ECT delirium were compared. Multiple logistic regression analysis was applied to analyze the correlation between variables and post-ECT delirium.Post-ECT delirium developed in 23 sessions (8.6%). Of all the demographic and clinical variables measured, only etomidate use was significantly different between delirium-positive and delirium-negative groups after Bonferroni correction. The regression model also indicated that etomidate use to be significantly associated with post-ECT delirium.In this study, etomidate was associated with a higher risk of developing post-ECT delirium, an association that appeared unrelated to other possible measured variables. Practitioners should take into account the risk of post-ECT delirium while choosing anesthetics, so as to prevent early discontinuation before sufficient therapeutic gain is achieved.

A multicenter investigation of the hemodynamic effects of induction agents for trauma rapid sequence intubation.

BACKGROUND: Several options exist for induction agents during rapid sequence intubation (RSI) in trauma patients, including etomidate, ketamine, and propofol. These drugs have reported variable hemodynamic effects (hypotension with propofol and sympathomimetic effects with ketamine) that could affect trauma resuscitations. The purpose of this study was to compare the hemodynamic effects of these three induction agents during emergency department RSI in adult trauma. We hypothesized that these drugs would display a differing hemodynamic profile during RSI. METHODS: We performed a retrospective (2014-2019), multicenter trial of adult (≥18 years) trauma patients admitted to eight ACS-verified Level I trauma centers who underwent emergency department RSI. Variables collected included systolic blood pressure (SBP) and pulse before and after RSI. The primary outcomes were change in heart rate and SBP before and after RSI. RESULTS: There were 2,092 patients who met criteria, 85% received etomidate (E), 8% ketamine (K), and 7% propofol (P). Before RSI, the ketamine group had a lower SBP (E, 135 vs. K, 125 vs. P, 135 mm Hg, p = 0.04) but there was no difference in pulse (E, 104 vs. K, 107 vs. P, 105 bpm, p = 0.45). After RSI, there were no differences in SBP (E, 135 vs. K, 130 vs. P, 133 mm Hg, p = 0.34) or pulse (E, 106 vs. K, 110 vs. P, 104 bpm, p = 0.08). There was no difference in the average change of SBP (E, 0.2 vs. K, 5.2 vs. P, -1.8 mm Hg, p = 0.4) or pulse (E, 1.7 vs. K, 3.5 bpm vs. P, -0.96, p = 0.24) during RSI. CONCLUSION: Contrary to our hypothesis, there was no difference in the hemodynamic effect for etomidate versus ketamine versus propofol during RSI in trauma patients. LEVEL OF EVIDENCE: Therapeutic, Level IV.

Clinical observation of the combined use of propofol and etomidate in painless gastroscopy.

OBJECTIVE: This study is aims to compare the anesthetic safety of propofol combined with etomidate for painless gastroscopy. METHODS: Three hundred patients undergoing painless gastroscopy were randomly assigned to P, PE1, and PE2 groups. Patients were anesthetized with propofol (P group) or propofol combined with etomidate (volume ratio 1: 1, PE1 group; volume ratio 2: 1, PE2 group). The hemodynamics and adverse reactions were observed. The sleep quality satisfaction and nature of dreams were recorded. RESULTS: Compared with pre-anesthesia, the mean arterial pressure and heart rate of the 3 groups were significantly slower during the examination and at the end of the examination. PE1 group had a higher incidence of muscle spasm, body moving, choking, and deglutition. The incidence of hypoxemia and injection pain was higher in P group. P and PE2 group had higher sleep quality satisfaction and dream incidence after awaking. However, there was no difference in the nature of dreams among 3 groups. CONCLUSION: Our data indicate that the combination of 10 ml 1.0% propofol and 5 ml 0.2% etomidate for painless gastroscopy reduces adverse reactions while not affecting the patients respiratory function. Moreover, it is safe and effective, which is worthy of clinical application and promotion.

A Comparison of Ketamine or Etomidate Combined with Xylazine for Intraperitoneal Anesthesia in Four Mouse Strains.

Intraperitoneal (IP) injection is a common route of anesthetic administration in mice. Ketamine-xylazine (KX) anesthesia is one of the most widely used IP protocols, but has limitations. Etomidate is an alternative to ketamine that has been used in both human and veterinary medicine yet has not been widely studied in mice. The purpose of this study was to evaluate etomidate-xylazine (EX) anesthesia as an alternative to KX. We hypothesized that EX would be as safe and effective as KX, with both sex- and strain-dependent differences. Male and female Crl:CD1(ICR), C57BL/6NCrl, BALB/cJ and NU/J mice were given a single IP dose of ketamine 100 mg/kg and xylazine 10 mg/kg or etomidate 20 mg/kg and xylazine 10 mg/kg. Sedation times were similar between KX and EX, with CD1 mice exhibiting shorter sedation times. Surgical anesthesia was achieved in 44% of EX mice, compared with 4% of KX mice. C57BL/6NCrl mice were significantly more likely to achieve surgical anesthesia when given EX (94%) or KX (18%) than were other strains. In all strains except C57BL/6NCrl mice, females were more likely to reach surgical anesthesia than males. Several mice experienced an adverse hyperexcitement response during induction, with BALB/cJ (79%) and NU/J (87%) mice given EX significantly more likely than other strains to experience hyperexcitement. EX and KX protocols had no overall differences in lowest respiration rate, lowest systolic blood pressure, lowest rectal temperature, or levels of acidosis, although the lowest heart rates were significantly higher with EX, indicating that EX and KX have similar safety profiles. Thus, EX and KX administration were associated with several significant physiologic differences when comparing sexes or individual strains. Our results indicate that EX is an equally effective sedative and a more effective surgical anesthetic than KX; however, EX is only recommended for invasive procedures in C57BL/6 mice due to the high rate of hyper-excitement and inconsistent surgical depth seen in other strains. Further study is needed to optimize EX for use in multiple mouse strains.

Drug dosing in the critically ill obese patient-a focus on sedation, analgesia, and delirium.

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.

Etomidate infusion at low doses is an effective and safe treatment for severe Cushing's syndrome outside intensive care.

INTRODUCTION: Intravenous etomidate infusion is effective to rapidly lower cortisol levels in severe Cushing's syndrome (CS) in the intensive care unit (ICU). Recently, etomidate treatment has also been proposed at lower doses in non-ICU wards, but it is not yet clear how this approach compares to ICU treatment. METHODS: We compared data from patients with severe CS treated with high starting doses of etomidate (median: 0.30 mg/kg BW/day) in ICU or with lower starting doses (median: 0.025 mg/kg BW/day) in non-ICU medical wards. RESULTS: Fourteen patients were included, among which ten were treated with low starting doses (LD) and four with high starting doses etomidate (HD). All patients had severe and complicated CS related to adrenal carcinoma (n = 8) or ectopic ACTH secretion (n = 6). Etomidate was effective in reducing cortisol levels below 500 nmol/L in a median of 1 day in the HD group compared to 3 days in the LD group (P = 0.013). However, all patients of the HD group had etomidate-induced cortisol insufficiency and needed frequent monitoring, while no patient from the LD group required hydrocortisone supplementation. No patient in either group died from complications of CS or etomidate treatment, but final outcome was poor as six patients in the LD group and all four patients in the HD group died from their cancer during follow-up. CONCLUSION: Our study suggests that, for patients with severe CS who do not require intensive organ-supporting therapy, the use of very low doses of etomidate in medical wards should be considered.

The Influence of Hemorrhagic Shock on the Disposition and Effects of Intravenous Anesthetics: A Narrative Review.

The need to reduce the dose of intravenous anesthetic in the setting of hemorrhagic shock is a well-established clinical dogma. Considered collectively,; the body of information concerning the behavior of intravenous anesthetics during hemorrhagic shock, drawn from animal and human data, confirms that clinical dogma and informs the rational selection and administration of intravenous anesthetics in the setting of hemorrhagic shock. The physiologic changes during hemorrhagic shock can alter pharmacokinetics and pharmacodynamics of intravenous anesthetics. Decreased size of the central compartment and central clearance caused by shock physiology lead to an altered dose-concentration relationship. For most agents and adjuncts, shock leads to substantially higher concentrations and increased effect. The notable exception is etomidate, which has relatively unchanged pharmacokinetics during shock. Increased concentrations lead to increased primary effect as well as increased side effects, notably cardiovascular effects. Pharmacokinetic changes are essentially reversed for all agents by fluid resuscitation. Propofol is unique among agents in that, in addition to the pharmacokinetic changes, it exhibits increased potency during shock. The pharmacodynamic changes of propofol persist despite fluid resuscitation. The persistence of these pharmacodynamic changes during shock is unlikely to be due to increased endogenous opiates, but is most likely due to increased fraction of unbound propofol. The stage of shock also appears to influence the pharmacologic changes. The changes are more rapid and pronounced as shock physiology progresses to the uncompensated stage. Although scant, human data corroborate the findings of animal studies. Both the animal and human data inform the rational selection and administration of intravenous anesthetics in the setting of hemorrhagic shock. The well-entrenched clinical dogma that etomidate is a preferred induction agent in patients experiencing hemorrhagic shock is firmly supported by the evidence. Propofol is a poor choice for induction or maintenance of anesthesia in severely bleeding patients, even with resuscitation; this can include emergent trauma cases or scheduled cases that routinely have mild or moderate blood loss.

Comparison of drugs used for intubation of pediatric trauma patients.

PURPOSE: Rapid sequence intubation (RSI) drugs, such as propofol, affect clinical outcomes, but this has not been examined in the pediatric population. This descriptive study compares the outcomes associated with intubation drugs used in pediatric traumatic brain injury (TBI) patients. METHODS: A retrospective chart review and descriptive analysis of intubated TBI patients, ages 0-17, admitted to Children's Hospital London Health Sciences Centre (LHSC) from January 2006-December 2016 was performed. RESULTS: Out of 259 patients intubated, complete data was available for 107 cases. Average injury severity score was 28; 46 were intubated at LHSC, 55 at primary care site, and 6 on scene. Intubation attempts were recorded in 87 of 107 paper charts. First-pass intubation success rate was 88.5%. Propofol (n = 21), midazolam (n = 31), etomidate (n = 13), and ketamine (n = 7) were the most commonly used intubation drugs. Paralytics were used in 50% of patients. Following use of propofol, Pediatric Adjusted Shock Index was increased as a result of worsening hypotension. Mean total hospital length of stay was 21 days with 7.5 days in ICU. Survival was 87%. CONCLUSION: Great variability exists in the use of induction agents and paralytics for RSI. Propofol was commonly used and is potentially associated with poorer clinical outcomes. TYPE OF STUDY: Retrospective. LEVEL OF EVIDENCE: IV.

The effects of a competitive antagonist on GABA-evoked currents in the presence of sedative-hypnotic agents.

BACKGROUND: Many sedative-hypnotic agents are thought to act by positively modulating γ-aminobutyric acid type A (GABAA) receptors. However, for many agents, the location(s) of the binding site(s) responsible for such receptor modulation is uncertain. We previously developed a low efficacy ligand (naphthalene-etomidate) that binds within a homologous set of hydrophobic cavities located at GABAA receptor subunit interfaces in the transmembrane domain, and thus acts as a competitive antagonist for higher efficacy sedative-hypnotics that also bind to these sites. In this report, we describe studies using this compound as a pharmacological screening tool to test whether sedative-hypnotics representing a range of chemical classes can modulate GABAA receptors by binding within these receptor cavities. METHODS: The impact of naphthalene-etomidate on GABA-evoked currents that were mediated by oocyte-expressed α1ß3γ2L GABAA receptors and potentiated by muscimol, alphaxalone, 2,2,2-trichloroethanol, isoflurane, AA29504, loreclezole, or diazepam was quantified using electrophysiological techniques. RESULTS: Naphthalene-etomidate (300 µM) significantly reduced GABAA receptor currents potentiated by alphaxalone (by 22 ± 11%), 2,2,2-trichloroethanol (by 23 ± 6%), isoflurane (by 32 ± 10%), AA29504 (by 41 ± 6%), loreclezole (by 43 ± 9%), but significantly increased those potentiated by muscimol (by 26 ± 11%). Naphthalene-etomidate significantly increased currents potentiated by a low (1 µM) diazepam concentration (by 56 ± 14%) while reducing those potentiated by a high (100 µM) diazepam concentration (by 11 ± 7%). CONCLUSIONS: Our results suggest that many (but not all) sedative-hypnotics are capable of positively modulating the GABAA receptor by binding within a common set of hydrophobic cavities.

Preclinical safety evaluation of ET-26 hydrochloride, a novel intravenous anesthetic agent, in beagle dogs.

ET-26 hydrochloride (ET-26HCl) is a novel etomidate analogue, approved for clinical trials, which has an effective sedative-hypnotic effect, a stable myocardial performance, and milder adrenocortical suppression than etomidate in rats and beagle dogs. Additionally, ET-26HCl showed similar hemodynamic stability as etomidate in the rat uncontrolled hemorrhagic shock model. Furthermore, ET-26HCl, in the rat lipopolysaccharide-induced sepsis model, was found to have a higher survival rate, a lower inflammatory reaction, and less organ injury. In the present study, we measured the potential adverse effects of ET-26HCl in beagle dogs in accordance with the Guidance on single- and repeated-dose toxicity published by the China Food and Drug Administration. In toxicity studies, single and repeated (14 days) intravenous doses of up to 16 mg/kg were well tolerated, with only pharmacologically related clinical signs seen in both studies. Thus, the no-observed-adverse-effect level (NOAEL) of ET-26HCl was found at 16 mg/kg/day. Toxicokinetic examination demonstrated that ET-26HCl showed a dose-dependent increase to exposure, no gender difference, and no evidence of accumulation. These results provide useful information for guiding a phase I clinical trial of ET-26HCl in healthy volunteers.

Simultaneous Determination of Etomidate and Its Major Metabolite, Etomidate Acid, in Urine Using Dilute and Shoot Liquid Chromatography-Tandem Mass Spectrometry.

Etomidate (ET) is a commonly used sedative-hypnotic agent such as propofol to induce anesthesia, and it is rapidly metabolized to etomidate acid (ETA) in liver. Herein, a simple method to determine ET and ETA in urine simultaneously was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A simple sample preparation method reduced the total analysis time. For all analytes, the separation was achieved in 6.5 min using reversed-phase chromatography with gradient elution. The best separation and detection of ETA was achieved using a porous graphitic carbon column. The column temperature was maintained at 30 °C to improve the efficiency and sensitivity. The calibration curves were linear over the concentration ranges of 0.4-120.0 ng/mL (ET) and 1.0-300.0 ng/mL (ETA), obtained with a weighting factor of 1/x2. The coefficients of determination (r2) were greater than 0.9958. The lower limits of quantification were 0.4 ng/mL (ET) and 1.0 ng/mL (ETA), intra-day (n = 6) and inter-day (n = 24) precision values for all compounds were less than 10.2% and 8.4%, respectively, while the intra- and inter-day accuracies were in the -9.9-2.9%, and -7.0-0.6%. The applicability of the method was examined by analyzing the urine samples obtained from ET users.

Binding site location on GABAA receptors determines whether mixtures of intravenous general anaesthetics interact synergistically or additively in vivo.

BACKGROUND AND PURPOSE: General anaesthetics can act on synaptic GABAA receptors by binding to one of three classes of general anaesthetic sites. Canonical drugs that bind selectively to only one class of site are etomidate, alphaxalone, and the mephobarbital derivative, R-mTFD-MPAB. We tested the hypothesis that the general anaesthetic potencies of mixtures of such site-selective agents binding to the same or to different sites would combine additively or synergistically respectively. EXPERIMENTAL APPROACH: The potency of general anaesthetics individually or in combinations to cause loss of righting reflexes in tadpoles was determined, and the results were analysed using isobolographic methods. KEY RESULTS: The potencies of combinations of two or three site-selective anaesthetics that all acted on a single class of site were strictly additive, regardless of which single site was involved. Combinations of two or three site-selective anaesthetics that all bound selectively to different sites always interacted synergistically. The strength of the synergy increased with the number of separate sites involved such that the percentage of each agent's EC50 required to cause anaesthesia was just 35% and 14% for two or three sites respectively. Propofol, which binds non-selectively to the etomidate and R-mTFD-MPAB sites, interacted synergistically with each of these agents. CONCLUSIONS AND IMPLICATIONS: The established pharmacology of the three anaesthetic binding sites on synaptic GABAA receptors was sufficient to predict whether a mixture of anaesthetics interacted additively or synergistically to cause loss of righting reflexes in vivo. The principles established here have implications for clinical practice.

Phospholipase C-related inactive protein type-1 deficiency affects anesthetic electroencephalogram activity induced by propofol and etomidate in mice.

PURPOSE: The general anesthetics propofol and etomidate mainly exert their anesthetic actions via GABA A receptor (GABAA-R). The GABAA-R activity is influenced by phospholipase C-related inactive protein type-1 (PRIP-1), which is related to trafficking and subcellular localization of GABAA-R. PRIP-1 deficiency attenuates the behavioral reactions to propofol but not etomidate. However, the effect of these anesthetics and of PRIP-1 deficiency on brain activity of CNS are still unclear. In this study, we examined the effects of propofol and etomidate on the electroencephalogram (EEG). METHODS: The cortical EEG activity was recorded in wild-type (WT) and PRIP-1 knockout (PRIP-1 KO) mice. All recorded EEG data were offline analyzed, and the power spectral density and 95% spectral edge frequency of EEG signals were compared between genotypes before and after injections of anesthetics. RESULTS: PRIP-1 deficiency induced increases in EEG absolute powers, but did not markedly change the relative spectral powers during waking and sleep states in the absence of anesthesia. Propofol administration induced increases in low-frequency relative EEG activity and decreases in SEF95 values in WT but not in PRIP-1 KO mice. Following etomidate injection, low-frequency EEG power was increased in both genotype groups. At high frequency, the relative power in PRIP-1 KO mice was smaller than that in WT mice. CONCLUSIONS: The lack of PRIP-1 disrupted the EEG power distribution, but did not affect the depth of anesthesia after etomidate administration. Our analyses suggest that PRIP-1 is differentially involved in anesthetic EEG activity with the regulation of GABAA-R activity.