Pharmacological interventions for reducing the incidence of myoclonus in patients receiving etomidate for induction of general anesthesia: an umbrella review.

OBJECTIVE: The objective of this umbrella review was to examine various pharmacologic interventions for their potential to reduce etomidate-induced myoclonus. A secondary objective was to compare the relative effectiveness of those medications in reducing the incidence of myoclonus when etomidate is utilized for the induction of general anesthesia. INTRODUCTION: Etomidate is the drug of choice when inducing general anesthesia in hemodynamically unstable patients. However, its use is limited among the general surgical population due to its ability to cause adrenal suppression, vomiting, and myoclonus. Myoclonus can lead to damage of muscle fibers, myalgias, and patient discomfort, and can also be detrimental in patients with low cardiac reserve. Several systematic reviews have reported on the effectiveness of various intravenous medications in reducing mild, moderate, and severe myoclonus; however, a more thorough examination of their influence was lacking. INCLUSION CRITERIA: This review included systematic reviews and meta-analyses of randomized controlled trials involving the use of pharmacologic interventions to reduce etomidate-induced myoclonus. Reviews in English and conducted after 1965 were considered for inclusion. METHODS: A comprehensive search of 11 databases was conducted to identify published and unpublished reviews up to March 2022. Critical appraisal was conducted by 2 independent reviewers using the standardized JBI appraisal tool. Quantitative findings were summarized according to the dose, timing of administration, and relative risk using a data matrix, and were synthesized in tabular format with supporting narrative text. Results were organized by severity of myoclonus (overall, mild, moderate, and severe) and by type of intervention. RESULTS: Eight systematic reviews were included in this umbrella review, which included 48 relevant studies, after removal of duplicates (3909 participants included in the primary studies). Five of the systematic reviews examined the effectiveness of various types of opioids in the prevention of myoclonus, and 3 systematic reviews examined the effectiveness of non-opioid interventions, such as lidocaine, midazolam, and dexmedetomidine. Seven reviews searched at least 4 databases for pertinent studies and specifically indicated that blinded reviewers appraised the articles. All reviews used a published and validated appraisal instrument. The overall quality of all included reviews was judged to be moderate to high. The absolute risk reduction indicating the effectiveness of the prophylactic medications ranged from 47% to 81% for mild, 52% to 92% for moderate, and 61% to 96% for severe myoclonus. Opioids demonstrated the most consistent and substantial effect on the reduction in myoclonus. CONCLUSIONS: All pharmacologic interventions identified in this review demonstrated a statistically significant reduction in the incidence of myoclonus. Future studies and reviews should focus on elucidating the particular dose range and timing that is most effective. Anesthesia providers should consider a pre-treatment dose of one of the medications described in this umbrella review as a means to reduce myoclonus and the untoward effects of that condition.

Remimazolam vs Etomidate: Haemodynamic Effects in Hypertensive Elderly Patients Undergoing Non-Cardiac Surgery.

Background: Remimazolam tosilate (RT) is a novel ultrashort-acting γ-aminobutyric acid subtype A (GABAA) agonist, with several advantages including rapid induction and recovery, stable haemodynamics, and mild respiratory inhibition. However, studies have not been conducted to explore the haemodynamic effects of RT in elderly hypertensive subjects undergoing non-cardiac surgery. Therefore, we sought to compare the effects of anaesthesia induction using different doses of RT and etomidate on the haemodynamics of this group of patients. Methods: Patients were recruited into this single-center, prospective, randomized, double-blind trial from October 2022 to June 2023. A total of 150 hypertensive elderly undergoing non-cardiac surgery were randomly assigned into 0.2 mg/kg RT group (Group RL), 0.3 mg/kg RT group (Group RH) and 0.3 mg/kg etomidate group (Group E). The primary outcome of the study was haemodynamic changes (mean arterial pressure fluctuation value -∆MAP and heart rate fluctuation value -∆HR) observed during anaesthesia induction. Secondary outcomes included incidence of adverse cardiovascular events and adverse drug reactions (injection pain and myoclonus), cumulative doses of vasoactive drugs and vital signs at different time points. Results: Patients in Group E and Group RL had significantly lower haemodynamic fluctuations (∆MAP), lower incidence of hypotension and cumulative dose of ephedrine than subjects in Group RH. Patients in groups RL and RH had significantly lower incidence of injection pain and myoclonus compared with patients in group E. The results showed no statistically significant differences in ∆HR, hypertension, bradycardia, tachycardia, and time to loss of eye-opening reflex and start of intubation, and vital signs at different time points among the three groups. Conclusion: Use of low-dose RT (0.2 mg/kg) for induction of non-cardiac surgical anaesthesia in elderly hypertensive patients is more effective in maintaining haemodynamic stability and has fewer adverse effects compared with etomidate.

Efficacy of Granisetron versus Sufentanil on Reducing Myoclonic Movements Following Etomidate: Double-blind, randomised clinical trial.

Objectives: This study aimed to reduce the intensity of myoclonus movements by comparing the effectiveness of granisetron and sufentanil in reducing the intensity of etomidate-induced myoclonic movements. Etomidate-induced myoclonus occurs in up to 85% of patients under general anaesthesia. This type of myoclonus can induce significant clinical and economic problems in patients with special conditions. Methods: This double-blind randomised clinical trial study consisted of 96 adult patients recruited between January and July 2021 from Mashhad University of Medical Sciences, Mashhad, Iran. Using block randomisation, subjects were divided into three groups of 32 patients: the group receiving granisetron 40 µg/kg (group G), the group receiving sufentanil 0.2 µg/kg (group S) and the control group who did not receive the pretreatment (group C). Patients received these medications as pretreatments 120 seconds before induction with etomidate. After the injection of etomidate with a dose of 0.3 mg/kg, the incidence of myoclonus was evaluated. After evaluating the myoclonus, the full dose of narcotics (fentanyl 1 µg/kg) and muscle relaxants (atracurium 0.5 mg/kg) were administered to patients and a suitable airway was established for them. Results: The findings indicated that granisetron reduced the intensity and incidence of myoclonic movements more than sufentanil. In addition, myoclonic movements were observed at a significantly higher intensity in the control group (P = 0.001). Conclusion: The results obtained from the current study indicate that granisetron and sufentanil as pretreatments are effective for reducing myoclonus in patients.

Low-dose nalmefene pretreatment reduces etomidate-induced myoclonus: A randomized, double-blind controlled trial.

BACKGROUND: This study compared the effectiveness of nalmefene and fentanyl in reducing the incidence and severity of etomidate-induced myoclonus. METHODS: One hundred fifty patients were randomized to receive 0.25ug/kg of nalmefene, 1ug/kg of fentanyl, or the same volume of normal saline 3 minutes prior to etomidate-induced anesthesia. The primary observational indexes were the severity level and incidence of etomidate-induced myoclonus, and the secondary observational index included blood pressure, heart rate, and the incidence of adverse effects from anesthesia induction to resuscitation, such as cough, chest wall rigidity, dizziness, nausea, pain after awakening, and intraoperative awareness. RESULTS: The incidence of myoclonus was significantly lower in the nalmefene group (8.0%) than in the fentanyl group (32.0%) (P = .003) and in the normal saline group (72.0%) (P = .000). The severity level of myoclonus in the nalmefene group was significantly lower than the fentanyl group (P = .001) and normal saline group (P = .000). Meanwhile, the incidences of cough and chest wall rigidity during anesthesia induction were significantly lower in the nalmefene group compared with the fentanyl group (P = .003, P = .027). There were no statistically significant differences in heart rate and mean arterial pressure among the 3 gruops (P > .05). There was no difference in the incidence of adverse effects among the 3 groups during recovery from anesthesia (P > .05). CONCLUSION: Intravenous injection of 0.25ug/kg of nalmefene 3 minutes prior to etomidate is more effective in preventing etomidate-induced myoclonus during general anesthesia than 1ug/kg of fentanyl.

Three Cases of Myoclonus Secondary to Ciprofloxacin: "Ciproclonus".

OBJECTIVES: Ciprofloxacin is a fluoroquinolone that is used for bacterial infections involving different systems. In some cases, ciprofloxacin was reported to induce myoclonus. METHODS: We performed a chart review of 3 patients with myoclonus secondary to ciprofloxacin and reviewed the literature for similar cases. Written consent for publication was obtained from each patient, and their identities were concealed for ethical reasons. RESULTS: We describe 3 cases of myoclonus secondary to ciprofloxacin, 2 males and a female aged 61, 26, and 48 years, respectively. The myoclonus appeared within 3 days of ciprofloxacin intake. In all 3 cases, ciprofloxacin was prescribed for urinary tract infection. Electroencephalogram and neuroimaging studies were normal and possible causes were excluded. Thus, ciprofloxacin was believed to be the underlying cause and hence it was withdrawn. The patients had complete recovery on follow-up. CONCLUSIONS: Although ciprofloxacin is widely prescribed for different infections, only 13 cases were reported to develop myoclonus secondary to ciprofloxacin. The mean age of patients was 62 years. Fifty-four percent of cases were males. Cessation of ciprofloxacin was the most common management course. All individuals fully recovered after ciprofloxacin withdrawal. The mechanism of ciprofloxacin-induced myoclonus is probably associated with γ-aminobutyric acid and glutamate pathways.

Polymyoclonus, ventricular fibrillation and Takotsubo after accidental spinal injection of tranexamic acid.

Several factors have been identified as contributing to medication administration errors, including look-alike, sound-alike (LASA) errors. LASA errors are important causes of serious adverse events arising from spinal injection of tranexamic acid, which can be confused with ampoules of local anaesthesia.We present a case of accidental injection of 250 mg of tranexamic acid rather than prilocaine during spinal anaesthesia. The patient developed lower extremities myoclonus, followed by generalised convulsions and ventricular fibrillation, that was reverted within 6 min. Severe cardiogenic shock requiring both inotropic and vasopressor therapy followed, along with a classic apical ballooning pattern on echocardiography and elevated myocardial injury markers, indicating Takotsubo cardiomyopathy. The patient's condition progressively improved to full recovery, and she was discharged from hospital after 1 month with no neurological deficit or cardiac dysfunction.To our knowledge, this is the 28th reported case of accidental spinal injection of tranexamic acid. We present a brief review of previously published cases.

Comparison of Remimazolam Tosilate and Etomidate on Hemodynamics in Cardiac Surgery: A Randomised Controlled Trial.

Background: Remimazolam tosilate (RT) is a new ultrashort-acting γ-aminobutyric acid subtype A (GABAA) 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.

Etomidate-Induced Myoclonus in Sprague-Dawley Rats Involves Neocortical Glutamate Accumulation and N -Methyl- d -Aspartate Receptor Activity.

BACKGROUND: Etomidate-induced myoclonus, a seizure-like movement, is of interest to anesthetists. However, its origin in the brain and its underlying mechanism remain unclear. METHODS: Adult male Sprague-Dawley rats were anesthetized with etomidate, propofol, or lidocaine plus etomidate. We assessed the incidence of myoclonus, behavioral scores, and levels of glutamate and γ-aminobutyric acid (GABA) in the neocortex and hippocampus. To determine the origin and how N -methyl- d -aspartate receptors (NMDARs) modulate etomidate-induced neuroexcitability, the local field potential and muscular tension were monitored. Calcium imaging in vitro and immunoblotting in vivo were conducted to investigate the mechanisms underlying myoclonus. RESULTS: The incidence of etomidate (1.5 mg/kg in vivo)-induced myoclonus was higher than that of propofol (90% vs 10%, P = .0010) and lidocaine plus etomidate (90% vs 20%, P = .0050). Etomidate at doses of 3.75 and 6 mg/kg decreased the mean behavioral score at 1 (mean difference [MD]: 1.80, 95% confidence interval [CI], 0.58-3.02; P = .0058 for both), 2 (MD: 1.60, 95% CI, 0.43-2.77; P = .0084 and MD: 1.70, 95% CI, 0.54-2.86; P = .0060), 3 (MD: 1.60, 95% CI, 0.35-2.85; P = .0127 and MD: 1.70, 95% CI, 0.46-2.94; P = .0091) minutes after administration compared to etomidate at a dose of 1.5 mg/kg. In addition, 0.5 and 1 µM etomidate in vitro increased neocortical intracellular calcium signaling; this signaling decreased when the concentration increased to 5 and 10 µM. Etomidate increased the glutamate level compared to propofol (mean rank difference: 18.20; P = .003), and lidocaine plus etomidate (mean rank difference: 21.70; P = .0002). Etomidate in vivo activated neocortical ripple waves and was positively correlated with muscular tension amplitude (Spearman's r = 0.785, P < .0001). Etomidate at 1.5 mg/kg decreased the K-Cl cotransporter isoform 2 (KCC2) level compared with propofol (MD: -1.15, 95% CI, -1.47 to -0.83; P < .0001) and lidocaine plus etomidate (MD: -0.64, 95% CI, -0.96 to -0.32; P = .0002), DL-2-amino-5-phosphopentanoic acid (AP5) suppressed these effects, while NMDA enhanced them. CONCLUSIONS: Etomidate-induced myoclonus or neuroexcitability is concentration dependent. Etomidate-induced myoclonus originates in the neocortex. The underlying mechanism involves neocortical glutamate accumulation and NMDAR modulation and myoclonus correlates with NMDAR-induced downregulation of KCC2 protein expression.

Etomidate-induced myoclonus correlates with the dysfunction of astrocytes and glutamate transporters in the neocortex of Sprague-Dawley rats.

OBJECTIVE: Etomidate-induced myoclonus is common in clinical anesthesia. Propofol and lidocaine, as other sedative hypnotic and anticonvulsant drugs, rarely induce myoclonus. The mechanism of the myoclonus remains unclear. MATERIALS AND METHODS: Eighty-four adult male Sprague-Dawley (SD) rats anesthetized intravenously with etomidate, propofol, or lidocaine plus etomidate were observed of the behavioral changes at 0, 1, 2, 3, 4 and 5 min after anesthesia. Five minutes later, glutamate levels were measured in the cerebrospinal fluid (CSF), neocortex and hippocampus. The mRNAs and proteins expression of EAAT1, EAAT2, and GFAP in the neocortex and hippocampus were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot and immunofluorescence staining. RESULTS: Etomidate increased the mean behavioral scores at different time points and the neocortical glutamate level compared with the propofol (p=0.0283) and the lidocaine plus etomidate group (p=0.0035); The correlation analysis revealed a strong correlation between the mean behavioral score and the neocortical glutamate content (Spearman's r=0.6638, p=0.0027). No significant difference was found in the EAAT1, EAAT2, or GFAP mRNAs in the neocortex and hippocampus among three groups; etomidate decreased EAAT1 (p=0.0416 and p=0.0127) and EAAT2 (p=0.0363 and p=0.0109) proteins but increased the GFAP (p=0.0145 and p=0.0149) protein in the neocortex compared to the propofol and lidocaine plus etomidate group. Furthermore, etomidate activated GFAP-positive cells in the neocortex, but conversely inhibited proteins of EAATs in motor cortex. CONCLUSIONS: Etomidate-induced myoclonus is associated with neocortical glutamate accumulation. Suppression of the astrogliosis in neocortex and promoting extracellular glutamate uptake by regulating glutamate transporters (EAATs) in the motor cortex may be the therapeutic target for prevention of etomidate-induced myoclonus.

Antimicrobial neurotoxicity: an under-recognised cause of delirium.

Antimicrobial associated encephalopathy (AAE) is a well-documented, though under recognised, adverse event associated with antimicrobial use. Clinical manifestations of AAE are varied, ranging from myoclonus and seizure to an encephalopathy with cerebellar signs. The phenotypic presentation of the encephalopathy syndrome is, in general, governed by the antimicrobial in question. Given its apparent rarity in everyday clinical practice, awareness of AAE is crucial for physicians. We describe a reversible encephalopathy characterised by confusion, myoclonus and stupor in a 76 year old gentleman on antimicrobial therapy for a peri-rectal abscess.

Comparison of the influence of low dose etomidate and propofol as priming dose on the incidence of etomidate induced myoclonus: a randomised, double-blind clinical trial.

BACKGROUND: Though hemodynamically stable, etomidate is known for its myoclonus side effect following induction. The main aim of this study is an effective attempt to decrease the incidence of myoclonus with a priming agent. METHODS: A prospective, double-blind study was carried out on 50 adults posted for elective surgery. After premedication, priming was done with etomidate 0.03 mg.kg-1 (Group E) and propofol 0.2 mg.kg-1 (Group P), i.e., 1/10th of induction dose. After 60 seconds of priming, patients were induced with etomidate by titrating dose over 60 seconds until loss of verbal command and eyelash reflex. The grading of myoclonus, induction dosage, and hemodynamics for 10 minutes post induction were recorded. RESULTS: In the study, only 4 cases had myoclonus. Grade 1 myoclonus was encountered in three cases of etomidate group, while only one case in the propofol group had grade 2 myoclonus which was not statistically significant (p-value: 0.12). There was a significant reduction in the etomidate induction dosage in both groups. CONCLUSION: Priming with etomidate and propofol is equally effective in reducing myoclonus with the added benefit of hemodynamic stability and reduction of an induction dose of etomidate (> 50%).