Nonhypnotic low-dose etomidate for rapid correction of hypercortisolaemia in cushing's syndrome

We determined the adrenostatic potential of low-dose nonhypnotic etomidate in six patients with Cushing's syndrome (ectopic Cushing's syndrome,n=2; Cushing's disease,n=3; bilateral adrenal adenoma,n=1). Etomidate was given as a continuous infusion for 32 h in a dose of 2.5 mg/h (n=5) or 0.3 mg/kg/h (n=3), respectively. Saline was given during a control period. The responsiveness to exogenous ACTH was studied during placebo and 7 and 31 h after commencing etomidate by administration of 250 µg 1–24 ACTH i.v. Etomidate (2.5 mg/h) led to a consistent decrease in serum cortisol in all patients from a mean of 39.4±13.3 to 21.1±5.7 µg/dl after 7 h (P<0.05 compared with placebo). After 24 h cortisol was reduced further to a mean steady state concentration of 12.3±5.7 µg/dl (P<0.05). At the end of the infusion period the cortisol increase in response to ACTH was reduced but not abolished. In contrast, a dose of 0.3 mg/kg/h etomidate induced unresponsiveness of serum cortisol to exogenous ACTH within 7 h. However, sedation was observed in two out of three patients at this dose, while during etomidate in a dose of 2.5 mg/h no side effects were seen. We conclude that low-dose non-hypnotic etomidate reduces serum cortisol to within the normal range in patients with Cushing's syndrome. The possibility to dissociate the adrenostatic effect of etomidate from its hypnotic action, the absence of side effects, and the i.v. route suggest that etomidate in a dose of 0.04–0.05 mg/kg/h may become the drug of choice for rapid initial control of hypercortisolism

GABAergic compensation in connexin36 knock-out mice evident during low-magnesium seizure-like event activity

Gap junctions within the cerebral cortex may facilitate cortical seizure formation by their ability to synchronize electrical activity. To investigate this, one option is to compare wild-type (WT) animals with those lacking the gene for connexin36 (Cx36 KO); the protein that forms neuronal gap junctions between cortical inhibitory cells. However, genetically modified knock-out animals may exhibit compensatory effects; with the risk that observed differences between WT and Cx36 KO animals could be erroneously attributed to Cx36 gap junction effects. In this study we investigated the effect of GABAA-receptor modulation (augmentation with 16 μM etomidate and blockade with 100 μM picrotoxin) on low-magnesium seizure-like events (SLEs) in mouse cortical slices. In WT slices, picrotoxin enhanced both the amplitude (49% increase, p = 0.0006) and frequency (37% increase, p = 0.005) of SLEs; etomidate also enhanced SLE amplitude (18% increase, p = 0.003) but reduced event frequency (25% decrease, p < 0.0001). In Cx36 KO slices, the frequency effects of etomidate and picrotoxin were preserved, but the amplitude responses were abolished. Pre-treatment with the gap junction blocker mefloquin in WT slices did not significantly alter the drug responses, indicating that the reduction in amplitude seen in the Cx36 KO mice was not primarily mediated by their lack of interneuronal gap junctions, but was rather due to pre-existing compensatory changes in these animals. Conclusions from studies comparing seizure characteristics between WT and Cx36 KO mice must be viewed with a degree of caution because of the possible confounding effect of compensatory neurophysiological changes in the genetically modified animals

Histamine release after intravenous application of short-acting hypnotics. A comparison of etomidate, Althesin (CT1341) and propanidid

The subject of histamine release was investigated in 16 volunteers by means of plasma histamine determination after the administration of etornidate, Althesin, propanidid, and Cremophor EL. Althesin and propanidid caused release of histamine in various degrees of frequency. Blood pressure changes were rather pronounced with both anaesthetic agents; tachycardia reached its maximum in the first and second minute, which seems to be an argument against histamine release as the underlying cause of this reaction. Histamine was, indeed, only released to such an extent (with the exception of one borderline case) that no clinical symptoms other than secretion of gastric juice and erythema were to be expected. After the application of etomidate and Cremophor EL an increase in plasma histamine was not detectable. Changes in the differential blood picture in terms of a decrease in basophils only occurred after Althesin and propanidid; not, however, after etomidate and Cremophor EL. Etomidate is, therefore, the first hypnotic drug for intravenous application which is unlikely to cause chemical histamine release

The general anaesthetic etomidate inhibits the excitability of mouse thalamocortical relay neurons by modulating multiple modes of GABA_A receptor-mediated inhibition

Modulation of thalamocortical (TC) relay neuron function has been implicated in the sedative and hypnotic effects of general anaesthetics. Inhibition of TC neurons is mediated predominantly by a combination of phasic and tonic inhibition, together with a recently described ‘spillover’ mode of inhibition, generated by the dynamic recruitment of extrasynaptic γ-aminobutyric acid (GABA)(A) receptors (GABA(A)Rs). Previous studies demonstrated that the intravenous anaesthetic etomidate enhances tonic and phasic inhibition in TC relay neurons, but it is not known how etomidate may influence spillover inhibition. Moreover, it is unclear how etomidate influences the excitability of TC neurons. Thus, to investigate the relative contribution of synaptic (α1β2γ2) and extrasynaptic (α4β2δ) GABA(A)Rs to the thalamic effects of etomidate, we performed whole-cell recordings from mouse TC neurons lacking synaptic (α1(0/0)) or extrasynaptic (δ(0/0)) GABA(A)Rs. Etomidate (3 μm) significantly inhibited action-potential discharge in a manner that was dependent on facilitation of both synaptic and extrasynaptic GABA(A)Rs, although enhanced tonic inhibition was dominant in this respect. Additionally, phasic inhibition evoked by stimulation of the nucleus reticularis exhibited a spillover component mediated by δ-GABA(A)Rs, which was significantly prolonged in the presence of etomidate. Thus, etomidate greatly enhanced the transient suppression of TC spike trains by evoked inhibitory postsynaptic potentials. Collectively, these results suggest that the deactivation of thalamus observed during etomidate-induced anaesthesia involves potentiation of tonic and phasic inhibition, and implicate amplification of spillover inhibition as a novel mechanism to regulate the gating of sensory information through the thalamus during anaesthetic states

High-throughput screening in larval zebrafish identifies novel potent sedative-hypnotics

BACKGROUND: Many general anesthetics were discovered empirically, but primary screens to find new sedative-hypnotics in drug libraries have not used animals, limiting the types of drugs discovered. The authors hypothesized that a sedative-hypnotic screening approach using zebrafish larvae responses to sensory stimuli would perform comparably to standard assays, and efficiently identify new active compounds. METHODS: The authors developed a binary outcome photomotor response assay for zebrafish larvae using a computerized system that tracked individual motions of up to 96 animals simultaneously. The assay was validated against tadpole loss of righting reflexes, using sedative-hypnotics of widely varying potencies that affect various molecular targets. A total of 374 representative compounds from a larger library were screened in zebrafish larvae for hypnotic activity at 10 µM. Molecular mechanisms of hits were explored in anesthetic-sensitive ion channels using electrophysiology, or in zebrafish using a specific reversal agent. RESULTS: Zebrafish larvae assays required far less drug, time, and effort than tadpoles. In validation experiments, zebrafish and tadpole screening for hypnotic activity agreed 100% (n = 11; P = 0.002), and potencies were very similar (Pearson correlation, r > 0.999). Two reversible and potent sedative-hypnotics were discovered in the library subset. CMLD003237 (EC50, ~11 µM) weakly modulated γ-aminobutyric acid type A receptors and inhibited neuronal nicotinic receptors. CMLD006025 (EC50, ~13 µM) inhibited both N-methyl-D-aspartate and neuronal nicotinic receptors. CONCLUSIONS: Photomotor response assays in zebrafish larvae are a mechanism-independent platform for high-throughput screening to identify novel sedative-hypnotics. The variety of chemotypes producing hypnosis is likely much larger than currently known.This work was supported by grants from Shanghai Jiaotong University School of Medicine, Shanghai, China, and the Chinese Medical Association, Beijing, China (both to Dr. Yang). The Department of Anesthesia, Critical Care and Pain Medicine of Massachusetts General Hospital, Boston, Massachusetts, supported this work through a Research Scholars Award and an Innovation Grant (both to Dr. Forman). Contributions to this research from the Boston University Center for Molecular Discovery, Boston, Massachusetts (to Drs. Porco, Brown, Schaus, and Xu, and to Mr. Trilles), were supported by a grant from the National Institutes of Health, Bethesda, Maryland (grant No. R24 GM111625). (Shanghai Jiaotong University School of Medicine, Shanghai, China; Chinese Medical Association, Beijing, China; Department of Anesthesia, Critical Care and Pain Medicine of Massachusetts General Hospital, Boston, Massachusetts; R24 GM111625 - National Institutes of Health, Bethesda, Maryland)Accepted manuscript2019-09-0

Safety and efficacy of etomidate and propofol anesthesia in elderly patients undergoing gastroscopy: A double-blind randomized clinical study

The aim of the present study is to compare the safety, efficacy and cost effectiveness of anesthetic regimens by compound, using etomidate and propofol in elderly patients undergoing gastroscopy. A total of 200 volunteers (65–79 years of age) scheduled for gastroscopy under anesthesia were randomly divided into the following groups: P, propofol (1.5–2.0 mg/kg); E, etomidate (0.15-0.2 mg/kg); P+E, propofol (0.75–1 mg/kg) followed by etomidate (0.075-0.1 mg/kg); and E+P, etomidate (0.075-0.01 mg/kg) followed by propofol (0.75–1 mg/kg). Vital signs and bispectral index were monitored at different time points. Complications, induction and examination time, anesthesia duration, and recovery and discharge time were recorded. At the end of the procedure, the satisfaction of patients, endoscopists and the anesthetist were evaluated. The recovery (6.1±1.2 h) and discharge times (24.8±2.8 h) in group E were significantly longer compared with groups P, P+E and E+P (P<0.05). The occurrence of injection pain in group P+E was significantly higher compared with the other three groups (P<0.05). In addition, the incidence of myoclonus and post-operative nausea and vomiting were significantly higher in group P+E compared with the other three groups (P<0.05). There was no statistical difference among the four groups with regards to the patients' immediate, post-procedure satisfaction (P>0.05). Furthermore, there was no difference in the satisfaction of anesthesia, as evaluated by the anesthetist and endoscopist, among the four groups (P>0.05). The present study demonstrates that anesthesia for gastroscopy in elderly patients can be safely and effectively accomplished using a drug regimen that combines propofol with etomidate. The combined use of propofol and etomidate has unique characteristics which improve hemodynamic stability, cause minimal respiratory depression and less side effects, provide rapid return to full activity and result in high levels of satisfaction

To Tube or Not to Tube? The Role of Intubation during Stroke Thrombectomy.

In the 10 years since the FDA first cleared the use of endovascular devices for the treatment of acute stroke, definitive evidence that such therapy improves outcomes remains lacking. The decision to intubate patients undergoing stroke thrombectomy impacts multiple variables that may influence outcomes after stroke. Three main areas where intubation may deleteriously affect acute stroke management include the introduction of delays in revascularization, fluctuations in peri-procedural blood pressure, and hypocapnia, resulting in cerebral vasoconstriction. In this mini-review, we discuss the evidence supporting these limitations of intubation during stroke thrombectomy and encourage neurohospitalists, neurocritical care specialists, and neurointerventionalists to carefully consider the decision to intubate during thrombectomy and provide strategies to avoid potential complications associated with its use in acute stroke

Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation.

Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity-a phenomenon known as paradoxical excitation. Previous studies have identified GABAA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABAA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish